NM_000171.4:c.1274T>A

Variant names:

• chr5-151822749-A-T
• rs747623314
• NM_000171.4:c.1274T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000171.4(GLRA1):​c.1274T>A​(p.Met425Lys) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M425V) 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: 9.11
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1274T>A	p.Met425Lys	missense_variant	Exon 9 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1298T>A	p.Met433Lys	missense_variant	Exon 9 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.1025T>A	p.Met342Lys	missense_variant	Exon 8 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.1322T>A	p.Met441Lys	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.1274T>A	p.Met425Lys	missense_variant	Exon 9 of 9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.1298T>A	p.Met433Lys	missense_variant	Exon 9 of 9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*1032T>A		non_coding_transcript_exon_variant	Exon 8 of 8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*1032T>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.97
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Benign	2.0	.;M
PhyloP100		9.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.24	B;B
Vest4		0.76
MutPred		0.83		.;Gain of methylation at M433 (P = 0.0075);
MVP		0.85
MPC		0.11
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.92
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: rs747623314; hg19: chr5-151202310;