rs760390019

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate

The NM_000171.4(GLRA1):​c.292G>A​(p.Asp98Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,876 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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

10
7
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 5-151859969-C-T is Pathogenic according to our data. Variant chr5-151859969-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 464186.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GLRA1NM_000171.4 linkc.292G>A p.Asp98Asn missense_variant Exon 4 of 9 ENST00000274576.9 NP_000162.2 P23415-2
GLRA1NM_001146040.2 linkc.292G>A p.Asp98Asn missense_variant Exon 4 of 9 NP_001139512.1 P23415-1
GLRA1NM_001292000.2 linkc.43G>A p.Asp15Asn missense_variant Exon 3 of 8 NP_001278929.1 Q14C71
GLRA1XM_047417105.1 linkc.340G>A p.Asp114Asn missense_variant Exon 4 of 9 XP_047273061.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GLRA1ENST00000274576.9 linkc.292G>A p.Asp98Asn missense_variant Exon 4 of 9 1 NM_000171.4 ENSP00000274576.5 P23415-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152086
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251420
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461790
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152086
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary hyperekplexia Pathogenic:1
Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 98 of the GLRA1 protein (p.Asp98Asn). This variant is present in population databases (rs760390019, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 25568133, 32332682). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as D70N. ClinVar contains an entry for this variant (Variation ID: 464186). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLRA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 25568133). This variant disrupts the p.Asp98 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30866851). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
27
DANN
Pathogenic
1.0
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
3.0
M;M
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.022
D;D
Polyphen
0.30
B;B
Vest4
0.99
MutPred
0.97
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.92
MPC
2.0
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.87
gMVP
0.94

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs760390019; hg19: chr5-151239530; COSMIC: COSV51008274; API