chr19-4280217-C-T

Variant summary

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

The NM_020209.4(SHD):​c.154C>T​(p.Arg52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SHD
NM_020209.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37
Variant links:
Genes affected
SHD (HGNC:30633): (Src homology 2 domain containing transforming protein D) Predicted to enable phosphotyrosine residue binding activity. [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=0.068125814).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHDNM_020209.4 linkc.154C>T p.Arg52Cys missense_variant Exon 1 of 6 ENST00000543264.7 NP_064594.3 Q96IW2
SHDNM_001372011.1 linkc.154C>T p.Arg52Cys missense_variant Exon 2 of 7 NP_001358940.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHDENST00000543264.7 linkc.154C>T p.Arg52Cys missense_variant Exon 1 of 6 1 NM_020209.4 ENSP00000446058.1 Q96IW2
SHDENST00000599689.1 linkc.154C>T p.Arg52Cys missense_variant Exon 1 of 5 5 ENSP00000470181.1 M0QYZ4

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152140
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000565
AC:
14
AN:
247718
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134760
show subpopulations
Gnomad AFR exome
AF:
0.0000638
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00110
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000902
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1461642
Hom.:
0
Cov.:
33
AF XY:
0.0000316
AC XY:
23
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00122
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152140
Hom.:
0
Cov.:
31
AF XY:
0.0000673
AC XY:
5
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 30, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.154C>T (p.R52C) alteration is located in exon 1 (coding exon 1) of the SHD gene. This alteration results from a C to T substitution at nucleotide position 154, causing the arginine (R) at amino acid position 52 to be replaced by a cysteine (C). 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
0.090
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;.
Eigen
Uncertain
0.23
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Uncertain
0.091
D
MetaRNN
Benign
0.068
T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.4
M;.
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-2.6
D;.
REVEL
Benign
0.12
Sift
Uncertain
0.015
D;.
Sift4G
Uncertain
0.033
D;D
Polyphen
1.0
D;.
Vest4
0.17
MVP
0.74
MPC
0.67
ClinPred
0.49
T
GERP RS
3.5
Varity_R
0.15
gMVP
0.22

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: rs780651125; hg19: chr19-4280214; API