rs75463357

Variant names:

• chr5-151828939-C-T
• rs75463357
• NM_000171.4:c.1041G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000171.4(GLRA1):​c.1041G>A​(p.Arg347Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,964 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 32)
  • Exomes 𝑓: 0.021 (393 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.45

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 5-151828939-C-T is Benign according to our data. Variant chr5-151828939-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 352310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151828939-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0153 (2326/152338) while in subpopulation NFE AF= 0.0235 (1598/68036). AF 95% confidence interval is 0.0225. There are 19 homozygotes in gnomad4. There are 1066 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.792G>A	p.Arg264Arg	synonymous_variant	Exon 7 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.1089G>A	p.Arg363Arg	synonymous_variant	Exon 8 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.1041G>A	p.Arg347Arg	synonymous_variant	Exon 8 of 9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*799G>A		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*799G>A		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2325 AN: 152220 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.0162 AC: 4076 AN: 251118 Hom.: 57 AF XY: 0.0166 AC XY: 2252 AN XY: 135702

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0207 AC: 30220 AN: 1461626 Hom.: 393 Cov.: 31 AF XY: 0.0201 AC XY: 14619 AN XY: 727122

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00400

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0153 AC: 2326 AN: 152338 Hom.: 19 Cov.: 32 AF XY: 0.0143 AC XY: 1066 AN XY: 74486

Gnomad4 AFR AF: 0.00440

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0193 Hom.: 17

Bravo AF: 0.0154

Asia WGS AF: 0.00260 AC: 11 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0252

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyperekplexia 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary hyperekplexia Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.5
DANN	Benign	0.67

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: rs75463357; hg19: chr5-151208500; COSMIC: COSV51012696;