X-124346149-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.-494G>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 0.407 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68

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=-0.89).
• BP6: Variant X-124346149-G-A is Benign according to our data. Variant chrX-124346149-G-A is described in ClinVar as [Benign]. Clinvar id 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.

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.-494G>A		5_prime_UTR_variant	2/5			P3
STAG2	ENST00000469481.1	n.454-65673G>A		intron_variant, non_coding_transcript_variant		3
SH2D1A	ENST00000635645.1	n.499-19612G>A		intron_variant, non_coding_transcript_variant		5
SH2D1A	ENST00000698112.1	n.499-19612G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.407 AC: 44954 AN: 110344 Hom.: 7025 Cov.: 22 AF XY: 0.385 AC XY: 12584 AN XY: 32650

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

Gnomad4 AFR AF: 0.520

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.390

Gnomad4 OTH AF: 0.420

Alfa AF: 0.392 Hom.: 19153

Bravo AF: 0.416

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	-0.89
Cadd	Benign	0.34
Dann	Benign	0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7357894; hg19: chrX-123479999;