Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000171.4(GLRA1):c.884G>A(p.Ser295Asn) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.73

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000171.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 5-151851418-C-T is Pathogenic according to our data. Variant chr5-151851418-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16074.Status of the report is no_assertion_criteria_provided, 0 stars.

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
GLRA1	NM_000171.4	MANE Select	c.884G>A	p.Ser295Asn	missense	Exon 7 of 9	NP_000162.2
GLRA1	NM_001146040.2		c.884G>A	p.Ser295Asn	missense	Exon 7 of 9	NP_001139512.1
GLRA1	NM_001292000.2		c.635G>A	p.Ser212Asn	missense	Exon 6 of 8	NP_001278929.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.884G>A	p.Ser295Asn	missense	Exon 7 of 9	ENSP00000274576.5
GLRA1	ENST00000455880.2	TSL:1	c.884G>A	p.Ser295Asn	missense	Exon 7 of 9	ENSP00000411593.2
GLRA1	ENST00000462581.6	TSL:1	n.*642G>A		non_coding_transcript_exon	Exon 6 of 8	ENSP00000430595.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00862

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperekplexia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.9

PhyloP100

7.7

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.70

Sift

Uncertain

0.016

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.94

MutPred

0.81

Loss of glycosylation at S295 (P = 0.0719)

MVP

0.91

MPC

2.0

ClinPred

0.98

GERP RS

5.2

Varity_R

0.77

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(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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rs267606848

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over