1-20722769-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001103161.2(SH2D5):​c.1055G>A​(p.Arg352His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000466 in 1,523,248 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 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

SH2D5
NM_001103161.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3382452).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH2D5NM_001103161.2 linkc.1055G>A p.Arg352His 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.1055G>A p.Arg352His missense_variant Exon 9 of 10 2 NM_001103161.2 ENSP00000406026.2 Q6ZV89-1
SH2D5ENST00000375031.5 linkc.803G>A p.Arg268His missense_variant Exon 8 of 9 2 ENSP00000364171.1 Q6ZV89-2
SH2D5ENST00000460804.5 linkn.786G>A non_coding_transcript_exon_variant Exon 5 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000723
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000242
AC:
4
AN:
165004
Hom.:
0
AF XY:
0.0000221
AC XY:
2
AN XY:
90504
show subpopulations
Gnomad AFR exome
AF:
0.000104
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000613
Gnomad NFE exome
AF:
0.0000271
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000467
AC:
64
AN:
1371036
Hom.:
0
Cov.:
31
AF XY:
0.0000385
AC XY:
26
AN XY:
674698
show subpopulations
Gnomad4 AFR exome
AF:
0.000131
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000172
Gnomad4 SAS exome
AF:
0.0000135
Gnomad4 FIN exome
AF:
0.0000204
Gnomad4 NFE exome
AF:
0.0000461
Gnomad4 OTH exome
AF:
0.0000534
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000723
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.000249
AC:
1
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.0000167
AC:
2
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 07, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1055G>A (p.R352H) alteration is located in exon 9 (coding exon 8) of the SH2D5 gene. This alteration results from a G to A substitution at nucleotide position 1055, causing the arginine (R) at amino acid position 352 to be replaced by a histidine (H). 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
0.075
BayesDel_addAF
Benign
-0.051
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.037
.;T
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.34
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.9
.;L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.72
N;N
REVEL
Benign
0.087
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.027
D;D
Polyphen
0.012
.;B
Vest4
0.59
MVP
0.67
MPC
0.45
ClinPred
0.15
T
GERP RS
2.8
Varity_R
0.085
gMVP
0.50

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: rs376876214; hg19: chr1-21049262; COSMIC: COSV56118393; COSMIC: COSV56118393; API