rs73285947

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000171.4(GLRA1):c.559+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,593,668 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 88 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 77 hom. )

Consequence

GLRA1
NM_000171.4 splice_region, intron

Scores

Splicing: ADA: 0.000009675

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0180

Publications

1 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 (BayesDel_noAF=-0.83).

BP6

Variant 5-151856293-A-C is Benign according to our data. Variant chr5-151856293-A-C is described in ClinVar as Benign. ClinVar VariationId is 352315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4 link	c.559+8T>G	splice_region_variant, intron_variant	Intron 5 of 8	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2 link	c.559+8T>G	splice_region_variant, intron_variant	Intron 5 of 8		NP_001139512.1	P23415-1
GLRA1	NM_001292000.2 link	c.310+8T>G	splice_region_variant, intron_variant	Intron 4 of 7		NP_001278929.1	Q14C71
GLRA1	XM_047417105.1 link	c.607+8T>G	splice_region_variant, intron_variant	Intron 5 of 8		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 link	c.559+8T>G	splice_region_variant, intron_variant	Intron 5 of 8	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 link	c.559+8T>G	splice_region_variant, intron_variant	Intron 5 of 8	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6 link	n.*317+8T>G	splice_region_variant, intron_variant	Intron 4 of 7	1		ENSP00000430595.1	E5RJ70
GLRA1	ENST00000471351.2 link	n.842+8T>G	splice_region_variant, intron_variant	Intron 5 of 7	1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2623

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0591

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00422

AC:

1061

AN:

251428

AF XY:

0.00305

show subpopulations

Gnomad AFR exome

AF:

0.0578

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00171

AC:

2472

AN:

1441426

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1060

AN XY:

718410

show subpopulations

African (AFR)

AF:

0.0613

AC:

2020

AN:

32968

American (AMR)

AF:

0.00316

AC:

141

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.000245

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000329

AC:

AN:

1094010

Other (OTH)

AF:

0.00408

AC:

243

AN:

59584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0173

AC:

2632

AN:

152242

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1208

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0591

AC:

2455

AN:

41518

American (AMR)

AF:

0.00876

AC:

134

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68018

Other (OTH)

AF:

0.0176

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

123

246

370

493

616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00907

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GLRA1-related disorder

Benign:1

Apr 10, 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). -

Hyperekplexia 1

Benign:1

Jan 12, 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. -

not provided

Benign:1

Aug 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary hyperekplexia

Benign:1

Feb 03, 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

-0.83

CADD

Benign

2.2

(source)

DANN

Benign

0.65

PhyloP100

-0.018

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000097

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.060

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