5-151859871-G-T

Position:

• chr5-151859871-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000171.4(GLRA1):​c.390C>A​(p.Asn130Lys) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.545

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.390C>A	p.Asn130Lys	missense_variant	4/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.390C>A	p.Asn130Lys	missense_variant	4/9		NP_001139512.1
GLRA1	NM_001292000.2	c.141C>A	p.Asn47Lys	missense_variant	3/8		NP_001278929.1
GLRA1	XM_047417105.1	c.438C>A	p.Asn146Lys	missense_variant	4/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.390C>A	p.Asn130Lys	missense_variant	4/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.390C>A	p.Asn130Lys	missense_variant	4/9	1		ENSP00000411593	A1
GLRA1	ENST00000471351.2	n.673C>A		non_coding_transcript_exon_variant	4/8	1
GLRA1	ENST00000462581.6	c.*148C>A		3_prime_UTR_variant, NMD_transcript_variant	3/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.20	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.97	D;D
Vest4		0.98
MutPred		0.86		Gain of methylation at N130 (P = 0.0126);Gain of methylation at N130 (P = 0.0126);
MVP		0.83
MPC		2.2
ClinPred		0.99	D
GERP RS		-7.8
Varity_R		0.94
gMVP		0.93

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: rs112970419; hg19: chr5-151239432;