rs116474260

Positions:

• chr5-151822915-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000274576.9(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. 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 ENST00000274576.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 38327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151822915-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1108G>A	p.Gly370Ser	missense_variant	9/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1132G>A	p.Gly378Ser	missense_variant	9/9		NP_001139512.1
GLRA1	NM_001292000.2	c.859G>A	p.Gly287Ser	missense_variant	8/8		NP_001278929.1
GLRA1	XM_047417105.1	c.1156G>A	p.Gly386Ser	missense_variant	9/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.1108G>A	p.Gly370Ser	missense_variant	9/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.1132G>A	p.Gly378Ser	missense_variant	9/9	1		ENSP00000411593	A1
GLRA1	ENST00000462581.6	c.*866G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1419 AN: 152124 Hom.: 7 Cov.: 31

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

GnomAD3 exomes AF: 0.00962 AC: 2412 AN: 250714 Hom.: 20 AF XY: 0.00972 AC XY: 1316 AN XY: 135442

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 SAS exome AF: 0.00526

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.: 32 AF XY: 0.0125 AC XY: 9074 AN XY: 726808

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00595

Gnomad4 ASJ exome AF: 0.00847

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00521

Gnomad4 FIN exome AF: 0.00573

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.00932 AC: 1419 AN: 152242 Hom.: 7 Cov.: 31 AF XY: 0.00928 AC XY: 691 AN XY: 74426

Gnomad4 AFR AF: 0.00246

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0140 Hom.: 38

Bravo AF: 0.00922

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.0100 AC: 1214

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1 Benign:6

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	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 -
Pathogenic, flagged submission	curation	GeneReviews	Oct 04, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2019	This variant is associated with the following publications: (PMID: 27535533, 26764160, 27884173, 10817489, 20981092, 25333069, 20631190) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

GLRA1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 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). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

Hereditary hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.82	D
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	T
GERP RS		4.2
Varity_R		0.21
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

Other links and lift over

dbSNP: rs116474260; hg19: chr5-151202476;