rs990545

Variant names:

• chrX-124346012-G-A
• rs990545
• ENST00000698113.1:c.-631G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-124346012-G-A
• chrX-124346012-G-C
• chrX-124346012-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

STAG2 Gene-Disease associations (from GenCC):

• Mullegama-Klein-Martinez syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000698113.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	ENST00000698113.1		c.-631G>A		5_prime_UTR	Exon 2 of 5	ENSP00000513571.1	O60880-1
	STAG2	ENST00000469481.1	TSL:3	n.454-65810G>A		intron	N/A
	SH2D1A	ENST00000635645.1	TSL:5	n.499-19749G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.460 AC: 50839 AN: 110494 Hom.: 8341 Cov.: 23

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

African (AFR) AF: 0.393 AC: 11942 AN: 30400

American (AMR) AF: 0.572 AC: 5987 AN: 10463

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1010 AN: 2624

East Asian (EAS) AF: 0.718 AC: 2495 AN: 3474

South Asian (SAS) AF: 0.542 AC: 1402 AN: 2588

European-Finnish (FIN) AF: 0.672 AC: 3900 AN: 5802

Middle Eastern (MID) AF: 0.303 AC: 64 AN: 211

European-Non Finnish (NFE) AF: 0.439 AC: 23162 AN: 52795

Other (OTH) AF: 0.446 AC: 676 AN: 1516

Alfa AF: 0.452 Hom.: 34238

Bravo AF: 0.461

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.38
PhyloP100		0.30

Splicing

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

Other links and lift over

dbSNP: rs990545; hg19: chrX-123479862;