X-124333893-G-C

Variant names:

• chrX-124333893-G-C
• rs775432134
• NM_001355534.2:c.976G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001355534.2(TEX13D):​c.976G>C​(p.Gly326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000565 in 353,860 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. 7/10 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000041 (0 hom. 0 hem.)
• Consequence: TEX13D NM_001355534.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 0 publications found

Genes affected

TEX13D (HGNC:52278): (TEX13 family member D) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

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]

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 Gene-Disease associations (from GenCC):

• X-linked lymphoproliferative disease due to SH2D1A deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096791714).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355534.2. 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
	TEX13D	NM_001355534.2	MANE Select	c.976G>C	p.Gly326Arg	missense	Exon 1 of 1	NP_001342463.1	A0A0J9YY54

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEX13D	ENST00000632372.3	TSL:6 MANE Select	c.976G>C	p.Gly326Arg	missense	Exon 1 of 1	ENSP00000488696.1	A0A0J9YY54
	STAG2	ENST00000469481.1	TSL:3	n.454-77929G>C		intron	N/A
	TEX13D	ENST00000635518.1	TSL:5	n.90-1459G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000910 AC: 1 AN: 109882 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome AF: 0.00000410 AC: 1 AN: 243978 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 69984

African (AFR) AF: 0.000150 AC: 1 AN: 6680

American (AMR) AF: 0.00 AC: 0 AN: 5725

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7077

East Asian (EAS) AF: 0.00 AC: 0 AN: 17768

South Asian (SAS) AF: 0.00 AC: 0 AN: 3287

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15975

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 991

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 171862

Other (OTH) AF: 0.00 AC: 0 AN: 14613

GnomAD4 genome AF: 0.00000910 AC: 1 AN: 109882 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32220

African (AFR) AF: 0.0000333 AC: 1 AN: 30075

American (AMR) AF: 0.00 AC: 0 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2623

East Asian (EAS) AF: 0.00 AC: 0 AN: 3439

South Asian (SAS) AF: 0.00 AC: 0 AN: 2503

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5947

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52402

Other (OTH) AF: 0.00 AC: 0 AN: 1477

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.2
DANN	Benign	0.37
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.097	T
PhyloP100		-0.26
Sift4G	Benign	0.16	T
Vest4		0.10
GERP RS		1.4
Varity_R		0.057
gMVP		0.025

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: rs775432134; hg19: chrX-123467743;