rs75463357

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000171.4(GLRA1):c.1041G>A(p.Arg347Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,964 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 19 hom., cov: 32)

Exomes 𝑓: 0.021 ( 393 hom. )

Consequence

GLRA1
NM_000171.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.45

Publications

5 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 5-151828939-C-T is Benign according to our data. Variant chr5-151828939-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 352310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0153 (2326/152338) while in subpopulation NFE AF = 0.0235 (1598/68036). AF 95% confidence interval is 0.0225. There are 19 homozygotes in GnomAd4. There are 1066 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4 link	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2 link	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9		NP_001139512.1	P23415-1
GLRA1	NM_001292000.2 link	c.792G>A	p.Arg264Arg	synonymous_variant	Exon 7 of 8		NP_001278929.1	Q14C71
GLRA1	XM_047417105.1 link	c.1089G>A	p.Arg363Arg	synonymous_variant	Exon 8 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 link	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 link	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6 link	n.*799G>A		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000430595.1	E5RJ70
GLRA1	ENST00000462581.6 link	n.*799G>A		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2325

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00442

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0235

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0162

AC:

4076

AN:

251118

AF XY:

0.0166

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0247

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0207

AC:

30220

AN:

1461626

Hom.:

393

Cov.:

AF XY:

0.0201

AC XY:

14619

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33476

American (AMR)

AF:

0.0121

AC:

541

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

527

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00400

AC:

345

AN:

86232

European-Finnish (FIN)

AF:

0.0172

AC:

918

AN:

53400

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0239

AC:

26556

AN:

1111824

Other (OTH)

AF:

0.0190

AC:

1146

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1483

2966

4449

5932

7415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0153

AC:

2326

AN:

152338

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1066

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00440

AC:

183

AN:

41564

American (AMR)

AF:

0.0144

AC:

221

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00498

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0156

AC:

166

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0235

AC:

1598

AN:

68036

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

250

375

500

625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0219

Hom.:

Bravo

AF:

0.0154

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0249

EpiControl

AF:

0.0252

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 29, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hyperekplexia 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 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. -

Hereditary hyperekplexia

Benign:1

Feb 04, 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

BayesDel_noAF

Benign

-0.24

CADD

Benign

8.5

(source)

DANN

Benign

0.67

PhyloP100

2.5

Mutation Taster

=96/4

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs75463357

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