rs116474260

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000171.4(GLRA1):c.1108G>A(p.Gly370Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0124 in 1,613,434 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G370G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0093 ( 7 hom., cov: 31)

Exomes 𝑓: 0.013 ( 130 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 3.92

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

hyperekplexia 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GLRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00745064).

BP6

Variant 5-151822915-C-T is Benign according to our data. Variant chr5-151822915-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00932 (1419/152242) while in subpopulation NFE AF = 0.0148 (1007/68012). AF 95% confidence interval is 0.014. There are 7 homozygotes in GnomAd4. There are 691 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4 link	c.1108G>A	p.Gly370Ser	missense_variant	Exon 9 of 9	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2 link	c.1132G>A	p.Gly378Ser	missense_variant	Exon 9 of 9		NP_001139512.1	P23415-1
GLRA1	NM_001292000.2 link	c.859G>A	p.Gly287Ser	missense_variant	Exon 8 of 8		NP_001278929.1	Q14C71
GLRA1	XM_047417105.1 link	c.1156G>A	p.Gly386Ser	missense_variant	Exon 9 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 link	c.1108G>A	p.Gly370Ser	missense_variant	Exon 9 of 9	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 link	c.1132G>A	p.Gly378Ser	missense_variant	Exon 9 of 9	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6 link	n.*866G>A		non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000430595.1	E5RJ70
GLRA1	ENST00000462581.6 link	n.*866G>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

AF:

0.00933

AC:

1419

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00962

AC:

2412

AN:

250714

AF XY:

0.00972

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00553

Gnomad ASJ exome

AF:

0.00889

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00598

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0127

AC:

18541

AN:

1461192

Hom.:

130

Cov.:

AF XY:

0.0125

AC XY:

9074

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

33454

American (AMR)

AF:

0.00595

AC:

266

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00847

AC:

221

AN:

26084

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39684

South Asian (SAS)

AF:

0.00521

AC:

449

AN:

86242

European-Finnish (FIN)

AF:

0.00573

AC:

306

AN:

53408

Middle Eastern (MID)

AF:

0.0279

AC:

161

AN:

5766

European-Non Finnish (NFE)

AF:

0.0147

AC:

16361

AN:

1111482

Other (OTH)

AF:

0.0114

AC:

688

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

925

1850

2774

3699

4624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

584

1168

1752

2336

2920

<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

AF:

0.00932

AC:

1419

AN:

152242

Hom.:

Cov.:

AF XY:

0.00928

AC XY:

691

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00246

AC:

102

AN:

41540

American (AMR)

AF:

0.00863

AC:

132

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00601

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1007

AN:

68012

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.00922

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0100

AC:

1214

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0155

EpiControl

AF:

0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 1

Pathogenic:1Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 1.473% (rs116474260, 1959/128696 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Gly370Ser variant, sometimes called p.Gly342Ser or p.Gly378Ser due to a difference in cDNA numbering, in GLRA1 has been identified in an individual with hyperekplexia and their unaffected parent (PMID: 10817489). This variant has also been identified in >1% of European (non-Finnish) chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Gly370Ser variant may not impact protein function (PMID: 10817489). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for hyperekplexia. -

Oct 04, 2012

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

not provided

Benign:2

Oct 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27535533, 26764160, 27884173, 10817489, 20981092, 25333069, 20631190) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: DM? in HGMD, frequency -

GLRA1-related disorder

Benign:1

Mar 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.075

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.9

.;L

PhyloP100

3.9

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.93

N;N

REVEL

Benign

0.24

Sift

Benign

0.11

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0

B;B

Vest4

0.25

MVP

0.77

MPC

0.050

ClinPred

0.015

GERP RS

4.2

Varity_R

0.21

gMVP

0.59

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over