X-124346297-C-T

Position:

• chrX-124346297-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000698113(SH2D1A):​c.-346C>T 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 0.463 in 311,225 control chromosomes in the GnomAD database, including 23,862 homozygotes. There are 45,311 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (7691 hom., 14806 hem., cov: 22)
  • Exomes 𝑓: 0.47 (16171 hom. 30505 hem.)
• Consequence: SH2D1A ENST00000698113 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.173

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-124346297-C-T is Benign according to our data. Variant chrX-124346297-C-T is described in ClinVar as [Benign]. Clinvar id is 367866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-124346297-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2D1A	ENST00000698113	c.-346C>T		5_prime_UTR_premature_start_codon_gain_variant	2/5			ENSP00000513571.1
SH2D1A	ENST00000698113	c.-346C>T		5_prime_UTR_variant	2/5			ENSP00000513571.1
STAG2	ENST00000469481.1	n.454-65525C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.443 AC: 48714 AN: 110010 Hom.: 7692 Cov.: 22 AF XY: 0.457 AC XY: 14781 AN XY: 32330

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.433

GnomAD4 exome AF: 0.475 AC: 95502 AN: 201157 Hom.: 16171 Cov.: 0 AF XY: 0.483 AC XY: 30505 AN XY: 63211

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.712

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.628

Gnomad4 NFE exome AF: 0.423

Gnomad4 OTH exome AF: 0.456

GnomAD4 genome AF: 0.443 AC: 48732 AN: 110068 Hom.: 7691 Cov.: 22 AF XY: 0.457 AC XY: 14806 AN XY: 32398

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.685

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.430

Alfa AF: 0.437 Hom.: 21987

Bravo AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked lymphoproliferative disease due to SH2D1A deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 22425739) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12164382; hg19: chrX-123480147;