Classification rationale

BA1BS1BP4 Benign

CREB3L3 c.313G>A

The CREB3L3 c.313G>A (p.Gly105Arg, p.G105R) variant has been reported in ClinVar as Benign with criteria provided by a single submitter representing 2 clinical laboratory submissions.¹ This variant is common in population databases, with gnomAD v2.1 showing a total allele frequency of 0.37177% and an East Asian allele frequency of 3.44274%, and gnomAD v4.1 showing a total allele frequency of 0.21551% and an East Asian allele frequency of 3.43413%, which is above the default benign population thresholds.² Computational evidence does not support a damaging effect, with SpliceAI predicting no significant splice impact (maximum delta score 0.02), REVEL 0.257, and BayesDel -0.423809.³

BA1 + BS1 + BP4 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_032607.3 · variants mapped to exon structure

CREB3L3 NM_032607.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone review Benign

This variant is too common for a rare pathogenic variant under the default non-VCEP benign stand-alone threshold. The East Asian allele frequency is 3.44274% in gnomAD v2.1 and 3.43413% in gnomAD v4.1, which are both above the BA1 threshold of 1.0%.

gnomAD v2.1 East Asian AF 0.0344274gnomAD v4.1 East Asian AF 0.0343413

gnomad_v2 ↗gnomad_v4 ↗

BS1 strong review Benign

This variant is more frequent than expected for a pathogenic CREB3L3 variant under the default non-VCEP strong benign frequency threshold. The East Asian allele frequency is 3.44274% in gnomAD v2.1 and 3.43413% in gnomAD v4.1, which are both above the BS1 threshold of 0.3%.

gnomAD v2.1 East Asian AF 0.0344274gnomAD v4.1 East Asian AF 0.0343413

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Multiple computational results support a benign interpretation rather than a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.257, and BayesDel is -0.423809.

SpliceAI max delta score 0.02REVEL score 0.257BayesDel score -0.423809

spliceai ↗

Assessed · not applied · 2 not met · 19 not assessed

Pathogenic

PS1 No evidence was identified showing that a different nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic.

PS2 No confirmed de novo occurrence with parental testing was identified for this variant.

PS3 No well-established functional study was identified showing a damaging effect of p.(Gly105Arg).

PS4 No case-control or affected-individual enrichment data were identified for this variant.

PM1 Available evidence does not establish codon 105 as a mutational hotspot or as part of a well-established critical functional domain without benign variation.

PM2 This variant is not absent from population databases and is not rare by generic non-VCEP thresholds.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.

PM5 No evidence was identified that a different missense change at the same codon has been established as pathogenic or likely pathogenic.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish that missense variation in CREB3L3 is a common disease mechanism in a gene with low benign missense variation.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype-specific clinical evidence was identified showing a presentation highly specific for a CREB3L3-related disorder in a person carrying this variant.

PP5 This criterion was not used because external assertions alone are not sufficient evidence without primary supporting data.

Benign

BS2 Although this variant is observed with homozygotes in population datasets, the available evidence does not establish the disease penetrance and phenotype context needed to apply BS2.

BS3 No well-established functional study was identified showing retained normal function for p.(Gly105Arg).

BS4 No non-segregation evidence was identified for this variant.

BP1 This is a missense variant, but the available evidence does not establish a gene-specific pattern showing that only truncating variants are typically pathogenic and that missense variation is predominantly benign.

BP2 No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP5 No evidence was identified for an alternative molecular cause that fully explains the observed phenotype in a person carrying this variant.

BP6 This criterion was not used because external benign assertions alone are not sufficient evidence without primary supporting data.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00215512; MAF= 0.21551%, 3478/1613834 alleles, homozygotes = 37) and has highest observed frequency in the East Asian population (AF= 0.0343413; MAF= 3.43413%, 1540/44844 alleles, homozygotes = 31); grpmax FAF= 0.0329142.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0037177; MAF= 0.37177%, 1047/281626 alleles, homozygotes = 14) and has highest observed frequency in the East Asian population (AF= 0.0344274; MAF= 3.44274%, 686/19926 alleles, homozygotes = 13); grpmax FAF= 0.0321736.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.22% · 3478 / 1,613,834
37 hom · FAF 3.3%

East Asian 1540 / 44,844	3.4% 31 hom
Remaining individuals 199 / 62,498	0.32% 2 hom
Admixed American 164 / 59,962	0.27% 3 hom
European (non-Finnish) 1389 / 1,179,984	0.12% 1 hom
Middle Eastern 7 / 6,060	0.12%
African/African American 68 / 74,942	0.091%
European (Finnish) 49 / 63,966	0.077%
South Asian 61 / 91,062	0.067%
Ashkenazi Jewish 1 / 29,606	0.0034%

+ 1 not observed (Amish)

gnomAD v2.1

0.37% · 1047 / 281,626
14 hom · FAF 3.2%

East Asian 686 / 19,926	3.4% 13 hom
Remaining individuals 25 / 7,212	0.35%
Admixed American 117 / 35,432	0.33% 1 hom
European (non-Finnish) 170 / 128,048	0.13%
European (Finnish) 17 / 25,110	0.068%
African/African American 15 / 24,938	0.06%
South Asian 17 / 30,606	0.056%

+ 1 not observed (Ashkenazi Jewish)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.257. BayesDel score = -0.423809.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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