rs376426309

chr5-151924500-A-G

Variant summary

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

The NM_000171.4(GLRA1):c.50T>C(p.Phe17Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000913 in 1,588,070 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F17L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.81

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=0.3677328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GLRA1	NM_000171.4 linkuse as main transcript	c.50T>C	p.Phe17Ser	missense_variant	1/9	ENST00000274576.9
GLRA1	NM_001146040.2 linkuse as main transcript	c.50T>C	p.Phe17Ser	missense_variant	1/9
GLRA1	NM_001292000.2 linkuse as main transcript	c.-72T>C		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.50T>C	p.Phe17Ser	missense_variant	1/9	1	NM_000171.4	P4	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.50T>C	p.Phe17Ser	missense_variant	1/9	1		A1	P23415-1
GLRA1	ENST00000471351.2 linkuse as main transcript	n.333T>C		non_coding_transcript_exon_variant	1/8	1
GLRA1	ENST00000462581.6 linkuse as main transcript	c.50T>C	p.Phe17Ser	missense_variant, NMD_transcript_variant	1/8	1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251212

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.0000969

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000926

AC:

133

AN:

1435886

Hom.:

Cov.:

AF XY:

0.0000893

AC XY:

AN XY:

716360

show subpopulations

Gnomad4 AFR exome

AF:

0.0000606

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000118

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperekplexia 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.50T>C (p.F17S) alteration is located in exon 1 (coding exon 1) of the GLRA1 gene. This alteration results from a T to C substitution at nucleotide position 50, causing the phenylalanine (F) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary hyperekplexia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 17 of the GLRA1 protein (p.Phe17Ser). This variant is present in population databases (rs376426309, gnomAD 0.009%). 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: 464189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLRA1 protein function. 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

0.16

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

0.10

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.70

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.029

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.67

P;P

Vest4

0.55

MVP

0.72

MPC

.;3.66727572043E-4

ClinPred

0.24

GERP RS

5.1

Varity_R

0.39

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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