rs121918411

chr5-151851420-C-Achr5-151851420-C-Gchr5-151851420-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_000171.4(GLRA1):c.882G>T(p.Gln294His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89

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 12 ACMG points.

• PS1: Transcript NM_000171.4 (GLRA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 16064
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.882G>T	p.Gln294His	missense_variant	7/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.882G>T	p.Gln294His	missense_variant	7/9
GLRA1	NM_001292000.2	c.633G>T	p.Gln211His	missense_variant	6/8
GLRA1	XM_047417105.1	c.930G>T	p.Gln310His	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.882G>T	p.Gln294His	missense_variant	7/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.882G>T	p.Gln294His	missense_variant	7/9	1		A1
GLRA1	ENST00000471351.2	n.1165G>T		non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*640G>T		3_prime_UTR_variant, NMD_transcript_variant	6/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.83		Gain of glycosylation at T292 (P = 0.0842);Gain of glycosylation at T292 (P = 0.0842);
MVP		0.90
MPC		2.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.98

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: rs121918411; hg19: chr5-151230981;