chr1-20722791-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001103161.2(SH2D5):​c.1033G>C​(p.Val345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SH2D5
NM_001103161.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.324
Variant links:
Genes affected
SH2D5 (HGNC:28819): (SH2 domain containing 5) Predicted to be active in postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15370312).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH2D5NM_001103161.2 linkc.1033G>C p.Val345Leu missense_variant Exon 9 of 10 ENST00000444387.7 NP_001096631.1 Q6ZV89-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH2D5ENST00000444387.7 linkc.1033G>C p.Val345Leu missense_variant Exon 9 of 10 2 NM_001103161.2 ENSP00000406026.2 Q6ZV89-1
SH2D5ENST00000375031.5 linkc.781G>C p.Val261Leu missense_variant Exon 8 of 9 2 ENSP00000364171.1 Q6ZV89-2
SH2D5ENST00000460804.5 linkn.764G>C non_coding_transcript_exon_variant Exon 5 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1033G>C (p.V345L) alteration is located in exon 9 (coding exon 8) of the SH2D5 gene. This alteration results from a G to C substitution at nucleotide position 1033, causing the valine (V) at amino acid position 345 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.029
.;T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.45
N
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.8
.;L
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.80
N;N
REVEL
Benign
0.12
Sift
Benign
0.047
D;D
Sift4G
Benign
0.080
T;T
Polyphen
0.042
.;B
Vest4
0.23
MutPred
0.62
.;Loss of sheet (P = 0.0817);
MVP
0.54
MPC
0.11
ClinPred
0.42
T
GERP RS
2.9
Varity_R
0.14
gMVP
0.54

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2054711795; hg19: chr1-21049284; API