Genetic Variant SHISA7:p.Thr272Pro (chr19-55440623-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001145176.2(SHISA7):c.814A>C(p.Thr272Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,249,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SHISA7
NM_001145176.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.334

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019463599).

BP6

Variant 19-55440623-T-G is Benign according to our data. Variant chr19-55440623-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2480929.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHISA7	NM_001145176.2 link	c.814A>C	p.Thr272Pro	missense_variant	Exon 2 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.814A>C	p.Thr272Pro	missense_variant	Exon 2 of 4	2	NM_001145176.2	ENSP00000365503.3		A6NL88
SHISA7	ENST00000416792.2 link	c.814A>C	p.Thr272Pro	missense_variant	Exon 2 of 5	5		ENSP00000401307.2		H7C1N4

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

151684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000381

AC:

AN:

26218

Hom.:

AF XY:

0.0000848

AC XY:

AN XY:

11792

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1097444

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

518188

show subpopulations

Gnomad4 AFR exome

AF:

0.000912

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:

0.0000683

GnomAD4 genome

AF:

0.000204

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.000725

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000185

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 06, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.027

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.39

M_CAP

Benign

0.0033

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.090

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

REVEL

Benign

0.067

Sift

Benign

0.41

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.075

MVP

0.030

ClinPred

0.062

GERP RS

-1.0

Varity_R

0.14

gMVP

0.14

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