rs74542605

Positions:

• chr5-151924527-C-A
• chr5-151924527-C-G
• chr5-151924527-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000171.4(GLRA1):​c.23G>T​(p.Arg8Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21830383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.23G>T	p.Arg8Leu	missense_variant	1/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.23G>T	p.Arg8Leu	missense_variant	1/9
GLRA1	NM_001292000.2	c.-99G>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.23G>T	p.Arg8Leu	missense_variant	1/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.23G>T	p.Arg8Leu	missense_variant	1/9	1		A1
GLRA1	ENST00000471351.2	n.306G>T		non_coding_transcript_exon_variant	1/8	1
GLRA1	ENST00000462581.6	c.23G>T	p.Arg8Leu	missense_variant, NMD_transcript_variant	1/8	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.89
Eigen	Benign	-0.19
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.77	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.96	N;N
REVEL	Benign	0.24
Sift	Benign	0.65	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.046	B;B
Vest4		0.43
MutPred		0.55		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.74
MPC		.;4.03417366996E-4
ClinPred		0.51	D
GERP RS		5.1
Varity_R		0.27
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74542605; hg19: chr5-151304088;