rs775599403

Positions:

• chr5-151822849-T-A
• chr5-151822849-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000274576.9(GLRA1):​c.1174A>T​(p.Asn392Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N392D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GLRA1 ENST00000274576.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1174A>T	p.Asn392Tyr	missense_variant	9/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1198A>T	p.Asn400Tyr	missense_variant	9/9		NP_001139512.1
GLRA1	NM_001292000.2	c.925A>T	p.Asn309Tyr	missense_variant	8/8		NP_001278929.1
GLRA1	XM_047417105.1	c.1222A>T	p.Asn408Tyr	missense_variant	9/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.1174A>T	p.Asn392Tyr	missense_variant	9/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.1198A>T	p.Asn400Tyr	missense_variant	9/9	1		ENSP00000411593	A1
GLRA1	ENST00000462581.6	c.*932A>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary hyperekplexia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GLRA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 392 of the GLRA1 protein (p.Asn392Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.016	D
MutationAssessor	Benign	0.55	.;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.94	P;P
Vest4		0.63
MutPred		0.36		.;Gain of phosphorylation at N400 (P = 0.0293);
MVP		0.90
MPC		0.16
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.15
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs775599403; hg19: chr5-151202410;