5-151924500-A-C

Variant names:

• chr5-151924500-A-C
• rs376426309
• NM_000171.4:c.50T>G

Variant summary

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

The NM_001292000.2(GLRA1):​c.-72T>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000696 in 1,435,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GLRA1 NM_001292000.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292000.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	NM_000171.4	MANE Select	c.50T>G	p.Phe17Cys	missense	Exon 1 of 9	NP_000162.2	P23415-2
	GLRA1	NM_001292000.2		c.-72T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001278929.1	Q14C71
	GLRA1	NM_001146040.2		c.50T>G	p.Phe17Cys	missense	Exon 1 of 9	NP_001139512.1	P23415-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.50T>G	p.Phe17Cys	missense	Exon 1 of 9	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.50T>G	p.Phe17Cys	missense	Exon 1 of 9	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000462581.6	TSL:1	n.50T>G		non_coding_transcript_exon	Exon 1 of 8	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435888 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 716362

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85734

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088224

Other (OTH) AF: 0.00 AC: 0 AN: 59512

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.049	D
Polyphen		0.95	P
Vest4		0.56
MutPred		0.43		Loss of helix (P = 0.079)
MVP		0.80
MPC		0.00040
ClinPred		0.90	D
GERP RS		5.1
PromoterAI		-0.032	Neutral
Varity_R		0.26
gMVP		0.60
Mutation Taster		=69/31	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: rs376426309; hg19: chr5-151304061;