NM_000171.4:c.23G>T

Variant names:

• chr5-151924527-C-A
• rs74542605
• NM_000171.4:c.23G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.-99G>T		5_prime_UTR_variant	Exon 1 of 8		NP_001278929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.23G>T	p.Arg8Leu	missense_variant	Exon 1 of 9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.23G>T		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000430595.1
GLRA1	ENST00000471351.2	n.306G>T		non_coding_transcript_exon_variant	Exon 1 of 8	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		4.9
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
PromoterAI		-0.046	Neutral
Varity_R		0.27
gMVP		0.62
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs74542605; hg19: chr5-151304088;