rs75463357

Positions:

chr5-151828939-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000171.4(GLRA1):c.1041G>A(p.Arg347=) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.45

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE
GLRA1	NM_000171.4 linkuse as main transcript	c.1041G>A	p.Arg347=	synonymous_variant	8/9	ENST00000274576.9
GLRA1	NM_001146040.2 linkuse as main transcript	c.1041G>A	p.Arg347=	synonymous_variant	8/9
GLRA1	NM_001292000.2 linkuse as main transcript	c.792G>A	p.Arg264=	synonymous_variant	7/8
GLRA1	XM_047417105.1 linkuse as main transcript	c.1089G>A	p.Arg363=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.1041G>A	p.Arg347=	synonymous_variant	8/9	1	NM_000171.4	P4	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.1041G>A	p.Arg347=	synonymous_variant	8/9	1		A1	P23415-1
GLRA1	ENST00000462581.6 linkuse as main transcript	c.*799G>A		3_prime_UTR_variant, NMD_transcript_variant	7/8	1

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2325

AN:

152220

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0166

AC XY:

2252

AN XY:

135702

show subpopulations

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.:

AF XY:

0.0201

AC XY:

14619

AN XY:

727122

show subpopulations

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.:

Cov.:

AF XY:

0.0143

AC XY:

1066

AN XY:

74486

show subpopulations

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.:

Bravo

AF:

0.0154

Asia WGS

AF:

0.00260

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	- -

Hyperekplexia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Hereditary hyperekplexia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over