5-151822708-T-G

Position:

• chr5-151822708-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000171.4(GLRA1):​c.1315A>C​(p.Lys439Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1315A>C	p.Lys439Gln	missense_variant	9/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1339A>C	p.Lys447Gln	missense_variant	9/9		NP_001139512.1
GLRA1	NM_001292000.2	c.1066A>C	p.Lys356Gln	missense_variant	8/8		NP_001278929.1
GLRA1	XM_047417105.1	c.1363A>C	p.Lys455Gln	missense_variant	9/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.1315A>C	p.Lys439Gln	missense_variant	9/9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.1339A>C	p.Lys447Gln	missense_variant	9/9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*1073A>C		non_coding_transcript_exon_variant	8/8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*1073A>C		3_prime_UTR_variant	8/8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251290 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461506 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hyperekplexia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 439 of the GLRA1 protein (p.Lys439Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GLRA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1037234). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLRA1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.0	.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.062	T;T
Sift4G	Benign	0.23	T;T
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.51		.;Loss of methylation at K447 (P = 2e-04);
MVP		0.90
MPC		0.34
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.45
gMVP		0.78

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: rs1050028851; hg19: chr5-151202269;