19-4280260-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.197C>T​(p.Pro66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SHD
NM_020209.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.330
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=0.08389789).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHDNM_020209.4 linkc.197C>T p.Pro66Leu missense_variant Exon 1 of 6 ENST00000543264.7 NP_064594.3 Q96IW2
SHDNM_001372011.1 linkc.197C>T p.Pro66Leu 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.197C>T p.Pro66Leu missense_variant Exon 1 of 6 1 NM_020209.4 ENSP00000446058.1 Q96IW2
SHDENST00000599689.1 linkc.197C>T p.Pro66Leu missense_variant Exon 1 of 5 5 ENSP00000470181.1 M0QYZ4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152180
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000814
AC:
2
AN:
245842
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133884
show subpopulations
Gnomad AFR exome
AF:
0.0000637
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:
0.00
Gnomad NFE exome
AF:
0.00000913
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461278
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
726926
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152180
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000965
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.197C>T (p.P66L) 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 197, causing the proline (P) at amino acid position 66 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
0.070
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
11
DANN
Benign
0.88
DEOGEN2
Benign
0.34
T;.
Eigen
Benign
-0.99
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.68
T;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.084
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-3.8
D;.
REVEL
Benign
0.053
Sift
Benign
0.10
T;.
Sift4G
Uncertain
0.041
D;D
Polyphen
0.0
B;.
Vest4
0.042
MutPred
0.13
Loss of methylation at K70 (P = 0.0478);Loss of methylation at K70 (P = 0.0478);
MVP
0.50
MPC
0.16
ClinPred
0.048
T
GERP RS
1.9
Varity_R
0.074
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs1002415225; hg19: chr19-4280257; API