rs111033623
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong
The NM_002351.5(SH2D1A):c.163C>T(p.Arg55*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000697917: Functional studies showed no signaling lymphocyte activation moleculeassociated protein (SAP) expression in NK cells and no (or limited) expression in T cells in XLP patients.". Synonymous variant affecting the same amino acid position (i.e. R55R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
SH2D1A
NM_002351.5 stop_gained
NM_002351.5 stop_gained
Scores
2
1
1
Clinical Significance
Conservation
PhyloP100: 1.14
Publications
22 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 syndromeInheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- Xq25 microduplication syndromeInheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 22 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PS3
PS3 evidence extracted from ClinVar submissions: SCV000697917: Functional studies showed no signaling lymphocyte activation moleculeassociated protein (SAP) expression in NK cells and no (or limited) expression in T cells in XLP patients.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-124365786-C-T is Pathogenic according to our data. Variant chrX-124365786-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SH2D1A | TSL:1 MANE Select | c.163C>T | p.Arg55* | stop_gained | Exon 2 of 4 | ENSP00000360181.5 | O60880-1 | ||
| SH2D1A | TSL:1 | c.163C>T | p.Arg55* | stop_gained | Exon 2 of 4 | ENSP00000353126.4 | O60880-4 | ||
| SH2D1A | TSL:1 | c.138-4445C>T | intron | N/A | ENSP00000513589.1 | O60880-6 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1063904Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 335730
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1063904
Hom.:
Cov.:
24
AF XY:
AC XY:
0
AN XY:
335730
African (AFR)
AF:
AC:
0
AN:
25783
American (AMR)
AF:
AC:
0
AN:
35150
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19146
East Asian (EAS)
AF:
AC:
0
AN:
30008
South Asian (SAS)
AF:
AC:
0
AN:
53310
European-Finnish (FIN)
AF:
AC:
0
AN:
40493
Middle Eastern (MID)
AF:
AC:
0
AN:
4053
European-Non Finnish (NFE)
AF:
AC:
0
AN:
811025
Other (OTH)
AF:
AC:
0
AN:
44936
GnomAD4 genome
GnomAD4 genome
Cov.:
22
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
X-linked lymphoproliferative disease due to SH2D1A deficiency (3)
1
-
-
not provided (1)
1
-
-
X-linked lymphoproliferative syndrome (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
D
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
Splicevardb
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -25
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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