X-124346649-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_002351.5(SH2D1A):c.7G>T(p.Ala3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 1,210,366 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 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 0.000035 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000064 (0 hom. 32 hem.)
• Consequence: SH2D1A NM_002351.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.880

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 -7 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.008988082).
• BP6: Variant X-124346649-G-T is Benign according to our data. Variant chrX-124346649-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1169457.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D1A	NM_002351.5	c.7G>T	p.Ala3Ser	missense_variant	1/4	ENST00000371139.9
SH2D1A	NM_001114937.3	c.7G>T	p.Ala3Ser	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D1A	ENST00000371139.9	c.7G>T	p.Ala3Ser	missense_variant	1/4	1	NM_002351.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112678 Hom.: 0 Cov.: 23 AF XY: 0.0000574 AC XY: 2 AN XY: 34824

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00111

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 27 AN: 183354 Hom.: 0 AF XY: 0.000177 AC XY: 12 AN XY: 67806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.00166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000638 AC: 70 AN: 1097635 Hom.: 0 Cov.: 30 AF XY: 0.0000882 AC XY: 32 AN XY: 363011

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000258

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112731 Hom.: 0 Cov.: 23 AF XY: 0.0000573 AC XY: 2 AN XY: 34887

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00112

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000103 Hom.: 5

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	6.9
Dann	Benign	0.64
DEOGEN2	Benign	0.34	T;.;.
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Benign	-0.025	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.14	N;N;.
REVEL	Uncertain	0.60
Sift	Benign	0.52	T;T;.
Sift4G	Benign	0.83	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.036
MVP		0.94
MPC		1.1
ClinPred		0.0049	T
GERP RS		1.3
Varity_R		0.14
gMVP		0.63

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: rs148554414; hg19: chrX-123480499; COSMIC: COSV63579895;