rs267606848

Positions:

• chr5-151851418-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a transmembrane_region Helical; Name=2 (size 20) in uniprot entity GLRA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 id is 16074.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-151851418-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.884G>A	p.Ser295Asn	missense_variant	7/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.884G>A	p.Ser295Asn	missense_variant	7/9		NP_001139512.1
GLRA1	NM_001292000.2	c.635G>A	p.Ser212Asn	missense_variant	6/8		NP_001278929.1
GLRA1	XM_047417105.1	c.932G>A	p.Ser311Asn	missense_variant	7/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.884G>A	p.Ser295Asn	missense_variant	7/9	1	NM_000171.4	ENSP00000274576.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00862 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.81		Loss of glycosylation at S295 (P = 0.0719);Loss of glycosylation at S295 (P = 0.0719);
MVP		0.91
MPC		2.0
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.97

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: rs267606848; hg19: chr5-151230979;