rs62636581

chr5-151822842-G-Achr5-151822842-G-Cchr5-151822842-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000171.4(GLRA1):c.1181C>T(p.Pro394Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00271 in 1,614,106 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P394R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 51 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 60 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.04

Variant links:

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039157867).

BP6

Variant 5-151822842-G-A is Benign according to our data. Variant chr5-151822842-G-A is described in ClinVar as [Benign]. Clinvar id is 352308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151822842-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GLRA1	NM_000171.4 linkuse as main transcript	c.1181C>T	p.Pro394Leu	missense_variant	9/9	ENST00000274576.9
GLRA1	NM_001146040.2 linkuse as main transcript	c.1205C>T	p.Pro402Leu	missense_variant	9/9
GLRA1	NM_001292000.2 linkuse as main transcript	c.932C>T	p.Pro311Leu	missense_variant	8/8
GLRA1	XM_047417105.1 linkuse as main transcript	c.1229C>T	p.Pro410Leu	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.1181C>T	p.Pro394Leu	missense_variant	9/9	1	NM_000171.4	P4	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.1205C>T	p.Pro402Leu	missense_variant	9/9	1		A1	P23415-1
GLRA1	ENST00000462581.6 linkuse as main transcript	c.*939C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2172

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0504

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

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:

0.000118

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00355

AC:

893

AN:

251406

Hom.:

AF XY:

0.00267

AC XY:

363

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0502

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00151

AC:

2204

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

937

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0555

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00354

GnomAD4 genome

AF:

0.0143

AC:

2177

AN:

152302

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1024

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0503

Gnomad4 AMR

AF:

0.00385

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00190

Hom.:

Bravo

AF:

0.0159

ESP6500AA

AF:

0.0490

AC:

216

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00448

AC:

544

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -

Hyperekplexia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

GLRA1-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2019

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

Hereditary hyperekplexia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.96

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.19

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.71

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.17

Sift

Benign

0.13

T;T

Sift4G

Benign

0.075

T;T

Polyphen

0.0

B;B

Vest4

0.25

MVP

0.90

MPC

0.050

ClinPred

0.019

GERP RS

5.0

Varity_R

0.085

gMVP

0.59

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