NM_032607.3:c.313G>A

CREB3L3 · NP_115996.1:p.(Gly105Arg) · NM_032607.3

GRCh37: chr19:4157148 G>A · GRCh38: chr19:4157151 G>A

Gene: CREB3L3 Transcript: NM_032607.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting benign

Variant details

Gene

CREB3L3

Transcript

NM_032607.3

Protein

NP_115996.1:p.(Gly105Arg)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is a missense change, p.(Gly105Arg), and does not fall into the generic PVS1 null-variant categories such as nonsense, frameshift, or canonical +/-1,2 splice variants. Although loss of function is considered a relevant disease mechanism for CREB3L3, the available PVS1 scaffold does not support applying PVS1 to this variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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	Not assessed	No confirmed de novo occurrence with parental testing was identified for this variant.
PS3	Not assessed	No well-established functional study was identified showing a damaging effect of p.(Gly105Arg).
PS4	Not assessed	No case-control or affected-individual enrichment data were identified for this variant.
PM1	Not assessed	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	Not met	This variant is not absent from population databases and is not rare by generic non-VCEP thresholds. In gnomAD v2.1 the total allele frequency is 0.37177% and the East Asian allele frequency is 3.44274%, and in gnomAD v4.1 the total allele frequency is 0.21551% and the East Asian allele frequency is 3.43413%; these values are above the default PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change or in-frame exon-level alteration.
PM5	Not assessed	No evidence was identified that a different missense change at the same codon has been established as pathogenic or likely pathogenic.
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	Available evidence does not establish that missense variation in CREB3L3 is a common disease mechanism in a gene with low benign missense variation.
PP3	Not met	Available computational evidence does not support 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, which do not provide supportive evidence for pathogenicity.	spliceai revel bayesdel
PP4	Not assessed	No phenotype-specific clinical evidence was identified showing a presentation highly specific for a CREB3L3-related disorder in a person carrying this variant.
PP5	Not assessed	This criterion was not used because external assertions alone are not sufficient evidence without primary supporting data.
BA1	Met	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 gnomad_v4
BS1	Met	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 gnomad_v4
BS2	Not assessed	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.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing retained normal function for p.(Gly105Arg).
BS4	Not assessed	No non-segregation evidence was identified for this variant.
BP1	Not assessed	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	Not assessed	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.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region without known function.
BP4	Met	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 revel bayesdel
BP5	Not assessed	No evidence was identified for an alternative molecular cause that fully explains the observed phenotype in a person carrying this variant.
BP6	Not assessed	This criterion was not used because external benign assertions alone are not sufficient evidence without primary supporting data.
BP7	N/A	This variant is a missense substitution rather than a synonymous or intronic change, so BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.