Genetic Variant GLRA1:p.Asn130Lys (chr5-151859871-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000171.4(GLRA1):c.390C>A(p.Asn130Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N130N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.545

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: Labcorp Genetics (formerly Invitae), G2P
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GLRA1 links:

ENSG00000302741 (HGNC:):

ENSG00000302741 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000171.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000171.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLRA1	NM_000171.4	MANE Select	c.390C>A	p.Asn130Lys	missense	Exon 4 of 9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2		c.390C>A	p.Asn130Lys	missense	Exon 4 of 9	NP_001139512.1	P23415-1
GLRA1	NM_001292000.2		c.141C>A	p.Asn47Lys	missense	Exon 3 of 8	NP_001278929.1	Q14C71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.390C>A	p.Asn130Lys	missense	Exon 4 of 9	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2	TSL:1	c.390C>A	p.Asn130Lys	missense	Exon 4 of 9	ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6	TSL:1	n.*148C>A		non_coding_transcript_exon	Exon 3 of 8	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.20

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.7

PhyloP100

-0.55

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.97

Vest4

0.98

MutPred

0.86

Gain of methylation at N130 (P = 0.0126)

MVP

0.83

MPC

2.2

ClinPred

0.99

GERP RS

-7.8

Varity_R

0.94

gMVP

0.93

Mutation Taster

=15/85

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over