dbSNP rs121918412: GLRA1:p.Lys304Glu (chr5-151851392-T-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_000171.4(GLRA1):c.910A>G(p.Lys304Glu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GLRA1
NM_000171.4 missense, splice_region

Scores

Splicing: ADA: 0.3206

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.84

Publications

7 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 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000171.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

PP5

Variant 5-151851392-T-C is Pathogenic according to our data. Variant chr5-151851392-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 16065.Status of the report is criteria_provided_single_submitter, 1 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.910A>G	p.Lys304Glu	missense splice_region	Exon 7 of 9	NP_000162.2
GLRA1	NM_001146040.2		c.910A>G	p.Lys304Glu	missense splice_region	Exon 7 of 9	NP_001139512.1
GLRA1	NM_001292000.2		c.661A>G	p.Lys221Glu	missense splice_region	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.910A>G	p.Lys304Glu	missense splice_region	Exon 7 of 9	ENSP00000274576.5
GLRA1	ENST00000455880.2	TSL:1	c.910A>G	p.Lys304Glu	missense splice_region	Exon 7 of 9	ENSP00000411593.2
GLRA1	ENST00000462581.6	TSL:1	n.*668A>G		splice_region non_coding_transcript_exon	Exon 6 of 8	ENSP00000430595.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000548

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyperekplexia 1

Pathogenic:2

Oct 04, 2012

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Jan 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.3

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.90

Sift

Uncertain

0.029

Sift4G

Uncertain

0.020

Polyphen

0.98

Vest4

0.94

MutPred

0.79

Loss of methylation at K304 (P = 0.0146)

MVP

0.89

MPC

2.4

ClinPred

0.99

GERP RS

5.2

Varity_R

0.75

gMVP

0.97

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.32

dbscSNV1_RF

Benign

0.49

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over