rs112970419

chr5-151859871-G-Achr5-151859871-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000171.4(GLRA1):c.390C>T(p.Asn130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,020 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (7 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-151859871-G-A is Benign according to our data. Variant chr5-151859871-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 352318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.545 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00599 (911/152212) while in subpopulation AFR AF= 0.0212 (879/41506). AF 95% confidence interval is 0.02. There are 13 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.390C>T	p.Asn130=	synonymous_variant	4/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.390C>T	p.Asn130=	synonymous_variant	4/9
GLRA1	NM_001292000.2	c.141C>T	p.Asn47=	synonymous_variant	3/8
GLRA1	XM_047417105.1	c.438C>T	p.Asn146=	synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.390C>T	p.Asn130=	synonymous_variant	4/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.390C>T	p.Asn130=	synonymous_variant	4/9	1		A1
GLRA1	ENST00000471351.2	n.673C>T		non_coding_transcript_exon_variant	4/8	1
GLRA1	ENST00000462581.6	c.*148C>T		3_prime_UTR_variant, NMD_transcript_variant	3/8	1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152094 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00147 AC: 370 AN: 251488 Hom.: 4 AF XY: 0.00102 AC XY: 138 AN XY: 135916

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000627 AC: 916 AN: 1461808 Hom.: 7 Cov.: 32 AF XY: 0.000527 AC XY: 383 AN XY: 727214

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00599 AC: 911 AN: 152212 Hom.: 13 Cov.: 32 AF XY: 0.00554 AC XY: 412 AN XY: 74424

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00221 Hom.: 2

Bravo AF: 0.00657

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2020

- -

Hereditary hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.69
Dann	Benign	0.66

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; COSMIC: COSV51027968;