2-170852781-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_000817.3(GAD1):c.1252G>T(p.Val418Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,614,030 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

GAD1
NM_000817.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

GAD1 (HGNC:4092): (glutamate decarboxylase 1) This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

GAD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19945809).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00101 (153/152204) while in subpopulation AMR AF= 0.0036 (55/15286). AF 95% confidence interval is 0.00284. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3 link	c.1252G>T	p.Val418Phe	missense_variant	Exon 13 of 17	ENST00000358196.8	NP_000808.2	Q99259-1A0A0S2Z3V5Q8IVA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8 link	c.1252G>T	p.Val418Phe	missense_variant	Exon 13 of 17	1	NM_000817.3	ENSP00000350928.3		Q99259-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.000541

AC:

136

AN:

251472

Hom.:

AF XY:

0.000589

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.000519

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000423

AC:

619

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

326

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000985

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.000297

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00101

AC:

153

AN:

152204

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.0000337

Hom.:

Bravo

AF:

0.00144

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with phenylalanine at codon 418 of the GAD1 protein (p.Val418Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs143058194, ExAC 0.08%). This missense change has been observed in individual(s) with GAD1-related disease (PMID: 28832565). ClinVar contains an entry for this variant (Variation ID: 332237). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAD1: BP4 -

Inborn genetic diseases

Uncertain:1

Feb 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1252G>T (p.V418F) alteration is located in exon 13 (coding exon 12) of the GAD1 gene. This alteration results from a G to T substitution at nucleotide position 1252, causing the valine (V) at amino acid position 418 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

GAD1-related disorder

Benign:1

May 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Benign

0.14

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.040

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.15

REVEL

Benign

0.26

Sift

Benign

0.39

Sift4G

Benign

0.34

Polyphen

0.98

Vest4

0.83

MVP

0.86

MPC

1.6

ClinPred

0.025

GERP RS

3.1

Varity_R

0.34

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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