dbSNP rs376426309: GLRA1:p.Phe17Cys (chr5-151924500-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000171.4(GLRA1):c.50T>G(p.Phe17Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F17S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.81

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4 link	c.50T>G	p.Phe17Cys	missense_variant	Exon 1 of 9	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001292000.2 link	c.-72T>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8		NP_001278929.1	Q14C71
GLRA1	NM_001146040.2 link	c.50T>G	p.Phe17Cys	missense_variant	Exon 1 of 9		NP_001139512.1	P23415-1
GLRA1	NM_001292000.2 link	c.-72T>G		5_prime_UTR_variant	Exon 1 of 8		NP_001278929.1	Q14C71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 link	c.50T>G	p.Phe17Cys	missense_variant	Exon 1 of 9	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 link	c.50T>G	p.Phe17Cys	missense_variant	Exon 1 of 9	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6 link	n.50T>G		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000430595.1	E5RJ70
GLRA1	ENST00000471351.2 link	n.333T>G		non_coding_transcript_exon_variant	Exon 1 of 8	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1435888

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33026

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

85734

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088224

Other (OTH)

AF:

0.00

AC:

AN:

59512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.34

N;N

PhyloP100

5.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.56

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.049

D;T

Polyphen

0.95

P;P

Vest4

0.56

MutPred

0.43

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.80

MPC

.;3.98175777942E-4

ClinPred

0.90

GERP RS

5.1

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.26

gMVP

0.60

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over