chrX-124370177-C-T

Position:

• chrX-124370177-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002351.5(SH2D1A):​c.203C>T​(p.Thr68Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SH2D1A NM_002351.5 missense, splice_region
• Scores: Splicing: ADA: 0.7610
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.24

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]

SH2D1A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain SH2 domain-containing protein 1A (size 127) in uniprot entity SH21A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_002351.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2D1A	NM_002351.5	c.203C>T	p.Thr68Ile	missense_variant, splice_region_variant	3/4	ENST00000371139.9	NP_002342.1
SH2D1A	NM_001114937.3	c.203C>T	p.Thr68Ile	missense_variant, splice_region_variant	3/4		NP_001108409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2D1A	ENST00000371139.9	c.203C>T	p.Thr68Ile	missense_variant, splice_region_variant	3/4	1	NM_002351.5	ENSP00000360181.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 18, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SH2D1A function (PMID: 11414741, 11477068). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 10905). This variant is also known as 502C>T. This missense change has been observed in individuals with X-linked recessive lymphoproliferative syndrome (PMID: 9771704, 11414741). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 68 of the SH2D1A protein (p.Thr68Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.79		Loss of disorder (P = 0.0185);Loss of disorder (P = 0.0185);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Pathogenic	0.84
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: rs111033627; hg19: chrX-123504027;