Genetic Variant GLRA1:p.Met425Lys (chr5-151822749-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000171.4(GLRA1):c.1274T>A(p.Met425Lys) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M425V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.11

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000171.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

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.1274T>A	p.Met425Lys	missense	Exon 9 of 9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2		c.1298T>A	p.Met433Lys	missense	Exon 9 of 9	NP_001139512.1	P23415-1
GLRA1	NM_001292000.2		c.1025T>A	p.Met342Lys	missense	Exon 8 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.1274T>A	p.Met425Lys	missense	Exon 9 of 9	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2	TSL:1	c.1298T>A	p.Met433Lys	missense	Exon 9 of 9	ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6	TSL:1	n.*1032T>A		non_coding_transcript_exon	Exon 8 of 8	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Benign

0.97

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.063

MutationAssessor

Benign

2.0

PhyloP100

9.1

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.010

Polyphen

0.24

Vest4

0.76

MutPred

0.83

Gain of methylation at M433 (P = 0.0075)

MVP

0.85

MPC

0.11

ClinPred

0.98

GERP RS

5.0

Varity_R

0.78

gMVP

0.92

Mutation Taster

=25/75

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