rs869320765

Positions:

• chr7-100200852-C-CCT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001282717.2(STAG3):​c.1947_1948dup​(p.Tyr650SerfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAG3 NM_001282717.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.45

Genes affected

STAG3 (HGNC:11356): (STAG3 cohesin complex component) The protein encoded by this gene is expressed in the nucleus and is a subunit of the cohesin complex which regulates the cohesion of sister chromatids during cell division. A mutation in this gene is associated with premature ovarian failure. Alternate splicing results in multiple transcript variants encoding distinct isoforms. This gene has multiple pseudogenes. [provided by RefSeq, Apr 2014]

CASTOR3P (HGNC:29954): (CASTOR family member 3, pseudogene) Predicted to be involved in cellular response to L-arginine and negative regulation of TORC1 signaling. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-100200852-C-CCT is Pathogenic according to our data. Variant chr7-100200852-C-CCT is described in ClinVar as [Pathogenic]. Clinvar id is 224903.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAG3	NM_001282717.2	c.1947_1948dup	p.Tyr650SerfsTer22	frameshift_variant	19/34	ENST00000615138.5
CASTOR3P	NR_028040.1	n.2664_2665insAG		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAG3	ENST00000615138.5	c.1947_1948dup	p.Tyr650SerfsTer22	frameshift_variant	19/34	1	NM_001282717.2	A2
CASTOR3P	ENST00000649671.1	n.2526_2527insAG		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian failure 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320765; hg19: chr7-99798475;