Starting

Initialising…

ZRSR2

Final classification

Likely Pathogenic

ZRSR2 c.376C>T · p.Arg126Ter

ZRSR2

The ZRSR2 c.376C>T (p.Arg126Ter) variant has been observed in somatic cancers in COSMIC (COSV57066630, n=5) and has not been reported in ClinVar.

Gene

ZRSR2

Transcript

NM_005089.3

HGVS · transcript:coding

NM_005089.3:c.376C>T

Consequence

N/A

GRCh38

chrX:15804174 C>T

GRCh37

chrX:15822297 C>T

Basis Generic ACMG/AMP 2015 final-classification combination rules (fallback), as indicated by final_classification_framework.json. ▾

Generic ACMG/AMP 2015 final-classification combination rules (fallback), as indicated by final_classification_framework.json.

Classification rationale

PVS1PM2 Likely Pathogenic

ZRSR2 c.376C>T

The ZRSR2 c.376C>T (p.Arg126Ter) variant has been observed in somatic cancers in COSMIC (COSV57066630, n=5) and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 that is below the 0.1% PM2 rarity threshold.² This is an early truncating variant in exon 5 of 11, predicted to create p.Arg126Ter at codon 126 of 483, and available gene-level literature supports loss of function as a disease mechanism for ZRSR2.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.10.⁴

PVS1 + PM2 → Likely Pathogenic

1 cosmic ↗

2 gnomad_v4 ↗

3 pvs1_gene_context

4 spliceai ↗

Gene diagram · NM_005089.3 · variants mapped to exon structure

ZRSR2 NM_005089.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57066630, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID 25645650

PMID 25645650 ↗

Found