chr5-151892407-G-T

Position:

chr5-151892407-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000171.4(GLRA1):c.88C>A(p.Arg30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

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 Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4212857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4 link	c.88C>A	p.Arg30Ser	missense_variant	2/9	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2 link	c.88C>A	p.Arg30Ser	missense_variant	2/9		NP_001139512.1	P23415-1
GLRA1	XM_047417105.1 link	c.136C>A	p.Arg46Ser	missense_variant	2/9		XP_047273061.1
GLRA1	NM_001292000.2 link	c.-65-5619C>A		intron_variant			NP_001278929.1	Q14C71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 link	c.88C>A	p.Arg30Ser	missense_variant	2/9	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 link	c.88C>A	p.Arg30Ser	missense_variant	2/9	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000471351.2 link	n.371C>A		non_coding_transcript_exon_variant	2/8	1
GLRA1	ENST00000462581.6 link	n.57-5619C>A		intron_variant		1		ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251054

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary hyperekplexia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2025

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 30 of the GLRA1 protein (p.Arg30Ser). This variant is present in population databases (rs369873008, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GLRA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573990). 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 not expected to disrupt GLRA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.42

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.34

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.39

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.29

T;T

Sift4G

Benign

0.63

T;T

Polyphen

1.0

D;D

Vest4

0.44

MVP

0.84

MPC

2.2

ClinPred

0.88

GERP RS

5.6

Varity_R

0.17

gMVP

0.54

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.

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