rs148554414

Variant names:

• chrX-124346649-G-A
• rs148554414
• NM_002351.5:c.7G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-124346649-G-A
• chrX-124346649-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_002351.5(SH2D1A):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,635 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: SH2D1A NM_002351.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.880
• Publications: 0 publications found

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]

STAG2 Gene-Disease associations (from GenCC):

• Mullegama-Klein-Martinez syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002351.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059407324).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002351.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	NM_002351.5	MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 4	NP_002342.1	O60880-1
	SH2D1A	NM_001114937.3		c.7G>A	p.Ala3Thr	missense	Exon 1 of 4	NP_001108409.1	O60880-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	ENST00000371139.9	TSL:1 MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 4	ENSP00000360181.5	O60880-1
	SH2D1A	ENST00000360027.5	TSL:1	c.7G>A	p.Ala3Thr	missense	Exon 1 of 4	ENSP00000353126.4	O60880-4
	SH2D1A	ENST00000494073.5	TSL:1	c.7G>A	p.Ala3Thr	missense	Exon 1 of 3	ENSP00000513589.1	O60880-6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097635 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363011

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841660

Other (OTH) AF: 0.00 AC: 0 AN: 46068

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.9
DANN	Benign	0.91
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.059	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.33	N
PhyloP100		0.88
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.15
Sift	Benign	0.49	T
Sift4G	Benign	0.65	T
Polyphen		0.0010	B
Vest4		0.048
MutPred		0.20		Gain of sheet (P = 0.1208)
MVP		0.97
MPC		1.1
ClinPred		0.028	T
GERP RS		1.3
PromoterAI		-0.063	Neutral
Varity_R		0.10
gMVP		0.63
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs148554414; hg19: chrX-123480499; COSMIC: COSV100758362;