Genetic Variant SHISA5:p.Val83Ile (chr3-48479244-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016479.6(SHISA5):c.247G>A(p.Val83Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SHISA5
NM_016479.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.48

Publications

0 publications found

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]

SHISA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04501468).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016479.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHISA5	NM_016479.6	MANE Select	c.247G>A	p.Val83Ile	missense	Exon 3 of 6	NP_057563.3
SHISA5	NM_001272065.3		c.226G>A	p.Val76Ile	missense	Exon 3 of 6	NP_001258994.1	Q8N114-5
SHISA5	NM_001272066.2		c.154G>A	p.Val52Ile	missense	Exon 3 of 6	NP_001258995.1	Q8N114-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHISA5	ENST00000296444.7	TSL:1 MANE Select	c.247G>A	p.Val83Ile	missense	Exon 3 of 6	ENSP00000296444.2	Q8N114-1
SHISA5	ENST00000949300.1		c.247G>A	p.Val83Ile	missense	Exon 3 of 6	ENSP00000619359.1
SHISA5	ENST00000929322.1		c.247G>A	p.Val83Ile	missense	Exon 3 of 6	ENSP00000599381.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39592

South Asian (SAS)

AF:

0.00

AC:

AN:

85488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110684

Other (OTH)

AF:

0.0000332

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0060

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.061

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.44

M_CAP

Benign

0.0034

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-2.5

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.070

REVEL

Benign

0.021

Sift

Benign

0.57

Sift4G

Benign

0.57

Polyphen

0.0

Vest4

0.12

MutPred

0.19

Gain of catalytic residue at P85 (P = 0.0379)

MVP

0.12

MPC

0.11

ClinPred

0.048

GERP RS

-7.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.37

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over