X-124346647-A-G

Position:

• chrX-124346647-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_002351.5(SH2D1A):​c.5A>G​(p.Asp2Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SH2D1A NM_002351.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.13

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain SH2 domain-containing protein 1A (size 127) in uniprot entity SH21A_HUMAN there are 24 pathogenic changes around while only 3 benign (89%) in NM_002351.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-124346647-A-G is Pathogenic according to our data. Variant chrX-124346647-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D1A	NM_002351.5	c.5A>G	p.Asp2Gly	missense_variant	1/4	ENST00000371139.9
SH2D1A	NM_001114937.3	c.5A>G	p.Asp2Gly	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D1A	ENST00000371139.9	c.5A>G	p.Asp2Gly	missense_variant	1/4	1	NM_002351.5	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.015	D;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.68	P;B;.
Vest4		0.33
MutPred		0.32		Gain of catalytic residue at M1 (P = 0.1091);Gain of catalytic residue at M1 (P = 0.1091);Gain of catalytic residue at M1 (P = 0.1091);
MVP		0.96
MPC		1.6
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.88

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: rs1556619319; hg19: chrX-123480497;