rs281864913

Positions:

chr5-151828950-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_StrongPP5

The NM_000171.4(GLRA1):c.1030C>T(p.Arg344*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.68

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 Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.237 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PP5

Variant 5-151828950-G-A is Pathogenic according to our data. Variant chr5-151828950-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242682.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4 linkuse as main transcript	c.1030C>T	p.Arg344*	stop_gained	8/9	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2 linkuse as main transcript	c.1030C>T	p.Arg344*	stop_gained	8/9		NP_001139512.1	P23415-1
GLRA1	NM_001292000.2 linkuse as main transcript	c.781C>T	p.Arg261*	stop_gained	7/8		NP_001278929.1	Q14C71
GLRA1	XM_047417105.1 linkuse as main transcript	c.1078C>T	p.Arg360*	stop_gained	8/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.1030C>T	p.Arg344*	stop_gained	8/9	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.1030C>T	p.Arg344*	stop_gained	8/9	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6 linkuse as main transcript	n.*788C>T		non_coding_transcript_exon_variant	7/8	1		ENSP00000430595.1	E5RJ70
GLRA1	ENST00000462581.6 linkuse as main transcript	n.*788C>T		3_prime_UTR_variant	7/8	1		ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251076

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000365

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary hyperekplexia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Arg344*) in the GLRA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the GLRA1 protein. This variant is present in population databases (rs281864913, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 15365143). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242682). This variant disrupts the p.Arg420 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10514101, 12169101, 19732286, 20631190, 25036534). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2021

Identified in patients with hyperekplexia who harbored a second GLRA1 variant on the opposite allele (in trans) in published literature (Zhang et al., 2020; Tsai et al., 2004); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 106 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 25036534, 10514101, 20631190, 25525159, 19732286, 12169101, 15365143, 32332682, 17641268) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.92

Vest4

0.90

GERP RS

4.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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