3-48479217-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016479.6(SHISA5):​c.274G>A​(p.Ala92Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,413,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

SHISA5
NM_016479.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.862
Variant links:
Genes affected
SHISA5 (HGNC:30376): (shisa family member 5) This gene encodes a member of the shisa family. The encoded protein is localized to the endoplasmic reticulum, and together with p53 induces apoptosis in a caspase-dependent manner. Alternative splicing results in multiple transcript variants. Related pseudogenes of this gene are found on chromosome X. [provided by RefSeq, Apr 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.054060012).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHISA5NM_016479.6 linkc.274G>A p.Ala92Thr missense_variant Exon 3 of 6 ENST00000296444.7 NP_057563.3 Q8N114-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHISA5ENST00000296444.7 linkc.274G>A p.Ala92Thr missense_variant Exon 3 of 6 1 NM_016479.6 ENSP00000296444.2 Q8N114-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD3 exomes
AF:
0.0000127
AC:
3
AN:
236198
Hom.:
0
AF XY:
0.0000233
AC XY:
3
AN XY:
128560
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000104
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000566
AC:
8
AN:
1413102
Hom.:
0
Cov.:
31
AF XY:
0.00000998
AC XY:
7
AN XY:
701556
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000896
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
Cov.:
30

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.274G>A (p.A92T) alteration is located in exon 3 (coding exon 3) of the SHISA5 gene. This alteration results from a G to A substitution at nucleotide position 274, causing the alanine (A) at amino acid position 92 to be replaced by a threonine (T). 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
0.092
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
2.5
DANN
Uncertain
0.99
DEOGEN2
Benign
0.086
.;T;.;.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.031
N
LIST_S2
Benign
0.63
T;T;.;.;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.054
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.0
.;M;.;.;.;.
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.89
.;N;N;N;N;N
REVEL
Benign
0.074
Sift
Benign
0.19
.;T;T;T;T;T
Sift4G
Benign
0.10
T;D;T;T;D;.
Polyphen
0.0010
.;B;.;.;.;.
Vest4
0.15
MutPred
0.22
.;Gain of glycosylation at A92 (P = 0.0199);.;.;.;.;
MVP
0.13
MPC
0.16
ClinPred
0.11
T
GERP RS
-2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.050
gMVP
0.64

Splicing

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: rs1473018571; hg19: chr3-48520626; COSMIC: COSV99604542; API