3-136338422-GCTCT-G

Position:

• chr3-136338422-GCTCT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The ENST00000383202.7(STAG1):​c.3697_3700del​(p.Arg1233LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STAG1 ENST00000383202.7 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.42

Genes affected

STAG1 (HGNC:11354): (STAG1 cohesin complex component) This gene is a member of the SCC3 family and is expressed in the nucleus. It encodes a component of cohesin, a multisubunit protein complex that provides sister chromatid cohesion along the length of a chromosome from DNA replication through prophase and prometaphase, after which it is dissociated in preparation for segregation during anaphase. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0212 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136338422-GCTCT-G is Pathogenic according to our data. Variant chr3-136338422-GCTCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817914.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAG1	NM_005862.3	c.3697_3700del	p.Arg1233LeufsTer3	frameshift_variant	33/34	ENST00000383202.7	NP_005853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAG1	ENST00000383202.7	c.3697_3700del	p.Arg1233LeufsTer3	frameshift_variant	33/34	1	NM_005862.3	ENSP00000372689	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2018

The c.3697_3700delAGAG variant in the STAG1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3697_3700delAGAG variant causes a frameshift starting with codon Arginine 1233, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Arg1233LeufsX3. This variant is predicted to cause loss of normal protein function through protein truncation. The c.3697_3700delAGAG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.3697_3700delAGAG as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1576367919; hg19: chr3-136057264;