5-151859802-A-T

Variant names:

• chr5-151859802-A-T
• rs575951950
• NM_000171.4:c.459T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000171.4(GLRA1):​c.459T>A​(p.Asn153Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. Synonymous variant affecting the same amino acid position (i.e. N153N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119
• Publications: 0 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

ENSG00000302741 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.459T>A	p.Asn153Lys	missense_variant	Exon 4 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.459T>A	p.Asn153Lys	missense_variant	Exon 4 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.210T>A	p.Asn70Lys	missense_variant	Exon 3 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.507T>A	p.Asn169Lys	missense_variant	Exon 4 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.459T>A	p.Asn153Lys	missense_variant	Exon 4 of 9	1	NM_000171.4	ENSP00000274576.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	0.26
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.84
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	0.18	N;N
PhyloP100		-0.12
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.29	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.97	D;P
Vest4		0.84
MutPred		0.63		Gain of methylation at N153 (P = 0.0158);Gain of methylation at N153 (P = 0.0158);
MVP		0.59
MPC		1.1
ClinPred		0.87	D
GERP RS		-10
Varity_R		0.32
gMVP		0.73
Mutation Taster		=25/75	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: rs575951950; hg19: chr5-151239363;