rs148700291

Variant names:

• chrX-124346519-T-A
• rs148700291
• ENST00000360027:c.-124T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-124346519-T-A
• chrX-124346519-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000360027(SH2D1A):​c.-124T>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 0.00101 in 792,860 control chromosomes in the GnomAD database, including 1 homozygotes. There are 219 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (1 hom. 201 hem.)
• Consequence: SH2D1A ENST00000360027 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.361

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-124346519-T-A is Benign according to our data. Variant chrX-124346519-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 367869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D1A	NM_002351.5	c.-124T>A		upstream_gene_variant		ENST00000371139.9	NP_002342.1
SH2D1A	NM_001114937.3	c.-124T>A		upstream_gene_variant			NP_001108409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D1A	ENST00000371139.9	c.-124T>A		upstream_gene_variant		1	NM_002351.5	ENSP00000360181.5

Frequencies

GnomAD3 genomes AF: 0.000884 AC: 99 AN: 111995 Hom.: 0 Cov.: 23 AF XY: 0.000527 AC XY: 18 AN XY: 34171

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000664

GnomAD4 exome AF: 0.00103 AC: 704 AN: 680811 Hom.: 1 Cov.: 11 AF XY: 0.00103 AC XY: 201 AN XY: 195465

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.000437

Gnomad4 ASJ exome AF: 0.0000601

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000653

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.000884 AC: 99 AN: 112049 Hom.: 0 Cov.: 23 AF XY: 0.000526 AC XY: 18 AN XY: 34235

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.000471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.000656

Alfa AF: 0.00124 Hom.: 6

Bravo AF: 0.000926

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked lymphoproliferative disease due to SH2D1A deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SH2D1A: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.9
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs148700291; hg19: chrX-123480369;