X-124346149-G-A

Variant names:

• chrX-124346149-G-A
• rs7357894
• ENST00000698113.1:c.-494G>A

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.-494G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 110,396 control chromosomes in the GnomAD database, including 7,024 homozygotes. There are 12,618 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.41 (7024 hom., 12618 hem., cov: 22)
• Consequence: SH2D1A ENST00000698113.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68
• Publications: 1 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=-0.89).
• BP6: Variant X-124346149-G-A is Benign according to our data. Variant chrX-124346149-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283992.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 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.-494G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000513571.1	O60880-1
	SH2D1A	ENST00000698113.1		c.-494G>A		5_prime_UTR	Exon 2 of 5	ENSP00000513571.1	O60880-1
	STAG2	ENST00000469481.1	TSL:3	n.454-65673G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.407 AC: 44954 AN: 110344 Hom.: 7025 Cov.: 22

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.534

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.424

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

GnomAD4 genome AF: 0.407 AC: 44977 AN: 110396 Hom.: 7024 Cov.: 22 AF XY: 0.386 AC XY: 12618 AN XY: 32712

African (AFR) AF: 0.520 AC: 15708 AN: 30224

American (AMR) AF: 0.319 AC: 3347 AN: 10493

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1228 AN: 2622

East Asian (EAS) AF: 0.242 AC: 842 AN: 3485

South Asian (SAS) AF: 0.342 AC: 872 AN: 2548

European-Finnish (FIN) AF: 0.227 AC: 1336 AN: 5889

Middle Eastern (MID) AF: 0.535 AC: 115 AN: 215

European-Non Finnish (NFE) AF: 0.390 AC: 20572 AN: 52740

Other (OTH) AF: 0.420 AC: 636 AN: 1516

Alfa AF: 0.396 Hom.: 28631

Bravo AF: 0.416

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	-0.89
CADD	Benign	0.34
DANN	Benign	0.57
PhyloP100		-1.7
PromoterAI		-0.0072	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7357894; hg19: chrX-123479999;