X-124346012-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000698113.1(SH2D1A):c.-631G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 110,551 control chromosomes in the GnomAD database, including 8,340 homozygotes. There are 15,518 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (8340 hom., 15518 hem., cov: 23)
• Consequence: SH2D1A ENST00000698113.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.305

Genes affected

SH2D1A (HGNC:10820): (SH2 domain containing 1A) This gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells. This protein contains an SH2 domain and a short tail. It associates with the signaling lymphocyte-activation molecule, thereby acting as an inhibitor of this transmembrane protein by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to its docking site. This protein can also bind to other related surface molecules that are expressed on activated T, B and NK cells, thereby modifying signal transduction pathways in these cells. Mutations in this gene cause lymphoproliferative syndrome X-linked type 1 or Duncan disease, a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus, with symptoms including severe mononucleosis and malignant lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

STAG2 (HGNC:11355): (STAG2 cohesin complex component) The protein encoded by this gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Targeted inactivation of this gene results in chromatid cohesion defects and aneuploidy, suggesting that genetic disruption of cohesin is a cause of aneuploidy in human cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-124346012-G-A is Benign according to our data. Variant chrX-124346012-G-A is described in ClinVar as [Benign]. Clinvar id is 1287179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D1A	ENST00000698113.1	c.-631G>A		5_prime_UTR_variant	2/5			P3
STAG2	ENST00000469481.1	n.454-65810G>A		intron_variant, non_coding_transcript_variant		3
SH2D1A	ENST00000635645.1	n.499-19749G>A		intron_variant, non_coding_transcript_variant		5
SH2D1A	ENST00000698112.1	n.499-19749G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.460 AC: 50839 AN: 110494 Hom.: 8341 Cov.: 23 AF XY: 0.473 AC XY: 15496 AN XY: 32734

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.460 AC: 50857 AN: 110551 Hom.: 8340 Cov.: 23 AF XY: 0.473 AC XY: 15518 AN XY: 32801

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.572

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.446

Alfa AF: 0.454 Hom.: 21258

Bravo AF: 0.461

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.5
Dann	Benign	0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs990545; hg19: chrX-123479862;