rs121918412

chr5-151851392-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000171.4(GLRA1):c.910A>G(p.Lys304Glu) variant causes a missense, splice region 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. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K304Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense, splice_region
• Scores: Splicing: ADA: 0.3206
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-151851392-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 5-151851392-T-C is Pathogenic according to our data. Variant chr5-151851392-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16065.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-151851392-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.910A>G	p.Lys304Glu	missense_variant, splice_region_variant	7/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.910A>G	p.Lys304Glu	missense_variant, splice_region_variant	7/9
GLRA1	NM_001292000.2	c.661A>G	p.Lys221Glu	missense_variant, splice_region_variant	6/8
GLRA1	XM_047417105.1	c.958A>G	p.Lys320Glu	missense_variant, splice_region_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.910A>G	p.Lys304Glu	missense_variant, splice_region_variant	7/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.910A>G	p.Lys304Glu	missense_variant, splice_region_variant	7/9	1		A1
GLRA1	ENST00000471351.2	n.1193A>G		splice_region_variant, non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*668A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.029	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.98	D;P
Vest4		0.94
MutPred		0.79		Loss of methylation at K304 (P = 0.0146);Loss of methylation at K304 (P = 0.0146);
MVP		0.89
MPC		2.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.32
dbscSNV1_RF	Benign	0.49
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: rs121918412; hg19: chr5-151230953;