rs121918417

Positions:

• chr5-151851525-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000171.4(GLRA1):​c.777C>G​(p.Ser259Arg) variant causes a missense change involving the alteration of a non-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:2
• Conservation: PhyloP100: 1.63

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 11) 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, 0.984
• PP5: Variant 5-151851525-G-C is Pathogenic according to our data. Variant chr5-151851525-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16071.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-151851525-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.777C>G	p.Ser259Arg	missense_variant	7/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.777C>G	p.Ser259Arg	missense_variant	7/9
GLRA1	NM_001292000.2	c.528C>G	p.Ser176Arg	missense_variant	6/8
GLRA1	XM_047417105.1	c.825C>G	p.Ser275Arg	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.777C>G	p.Ser259Arg	missense_variant	7/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.777C>G	p.Ser259Arg	missense_variant	7/9	1		A1
GLRA1	ENST00000471351.2	n.1060C>G		non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*535C>G		3_prime_UTR_variant, NMD_transcript_variant	6/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Hyperekplexia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2002	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.94		Gain of MoRF binding (P = 0.0635);Gain of MoRF binding (P = 0.0635);
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121918417; hg19: chr5-151231086;