rs759799079

Variant names:

• chr5-151822687-C-A
• rs759799079
• NM_000171.4:c.1336G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-151822687-C-A
• chr5-151822687-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000171.4(GLRA1):​c.1336G>T​(p.Val446Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V446I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1336G>T	p.Val446Phe	missense_variant	Exon 9 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1360G>T	p.Val454Phe	missense_variant	Exon 9 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.1087G>T	p.Val363Phe	missense_variant	Exon 8 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.1384G>T	p.Val462Phe	missense_variant	Exon 9 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.1336G>T	p.Val446Phe	missense_variant	Exon 9 of 9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.1360G>T	p.Val454Phe	missense_variant	Exon 9 of 9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*1094G>T		non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*1094G>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	.;L
PhyloP100		1.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.97	D;P
Vest4		0.63
MutPred		0.35		.;Loss of helix (P = 0.1706);
MVP		0.87
MPC		0.065
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.25
gMVP		0.90
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs759799079; hg19: chr5-151202248;