Genetic Variant SHISA7:p.Ala481Ser (chr19-55433332-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001145176.2(SHISA7):c.1441G>T(p.Ala481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000975 in 1,435,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

SHISA7
NM_001145176.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

Variant links:

Genes affected

SHISA7 (HGNC:35409): (shisa family member 7) Predicted to enable GABA receptor binding activity and ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including gamma-aminobutyric acid receptor clustering; regulation of signaling receptor activity; and regulation of synaptic plasticity. Predicted to be located in asymmetric, glutamatergic, excitatory synapse. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in glutamatergic synapse; postsynaptic density; and synaptic membrane. Predicted to be integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHISA7 links:

Genome browser will be placed here

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=0.036653996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHISA7	NM_001145176.2 link	c.1441G>T	p.Ala481Ser	missense_variant	Exon 4 of 4	ENST00000376325.10	NP_001138648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHISA7	ENST00000376325.10 link	c.1441G>T	p.Ala481Ser	missense_variant	Exon 4 of 4	2	NM_001145176.2	ENSP00000365503.3		A6NL88
SHISA7	ENST00000416792.2 link	c.1507G>T	p.Ala503Ser	missense_variant	Exon 5 of 5	5		ENSP00000401307.2		H7C1N4

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

35696

Hom.:

AF XY:

0.0000493

AC XY:

AN XY:

20272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000462

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000857

AC:

AN:

1283550

Hom.:

Cov.:

AF XY:

0.00000795

AC XY:

AN XY:

629050

show subpopulations

Gnomad4 AFR exome

AF:

0.0000394

Gnomad4 AMR exome

AF:

0.000251

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:

0.00000289

Gnomad4 OTH exome

AF:

0.0000375

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1441G>T (p.A481S) alteration is located in exon 4 (coding exon 4) of the SHISA7 gene. This alteration results from a G to T substitution at nucleotide position 1441, causing the alanine (A) at amino acid position 481 to be replaced by a serine (S). 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

-0.41

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.0030

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.50

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.12

REVEL

Benign

0.031

Sift

Benign

0.51

Sift4G

Benign

0.66

Polyphen

0.099

Vest4

0.10

MutPred

0.16

Gain of glycosylation at A481 (P = 0.0085);

MVP

0.040

ClinPred

0.042

GERP RS

3.0

Varity_R

0.094

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over