rs561848502

Positions:

• chr5-151859812-C-G
• chr5-151859812-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000171.4(GLRA1):​c.449G>C​(p.Arg150Pro) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.65

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.449G>C	p.Arg150Pro	missense_variant	4/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.449G>C	p.Arg150Pro	missense_variant	4/9		NP_001139512.1
GLRA1	NM_001292000.2	c.200G>C	p.Arg67Pro	missense_variant	3/8		NP_001278929.1
GLRA1	XM_047417105.1	c.497G>C	p.Arg166Pro	missense_variant	4/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.449G>C	p.Arg150Pro	missense_variant	4/9	1	NM_000171.4	ENSP00000274576.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2018

This sequence change replaces arginine with proline at codon 150 of the GLRA1 protein (p.Arg150Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GLRA1-related disease. 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. 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Benign	0.89
Eigen	Benign	0.058
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.73	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.98	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.63	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.81	P;P
Vest4		0.80
MutPred		0.59		Loss of MoRF binding (P = 0.0045);Loss of MoRF binding (P = 0.0045);
MVP		0.83
MPC		1.3
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.23
gMVP		0.63

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: rs561848502; hg19: chr5-151239373;