rs73285947

Positions:

• chr5-151856293-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000171.4(GLRA1):​c.559+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,593,668 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (88 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (77 hom.)
• Consequence: GLRA1 NM_000171.4 splice_region, intron
• Scores: Splicing: ADA: 0.000009675
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0180

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-151856293-A-C is Benign according to our data. Variant chr5-151856293-A-C is described in ClinVar as [Benign]. Clinvar id is 352315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151856293-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.559+8T>G		splice_region_variant, intron_variant		ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.559+8T>G		splice_region_variant, intron_variant			NP_001139512.1
GLRA1	NM_001292000.2	c.310+8T>G		splice_region_variant, intron_variant			NP_001278929.1
GLRA1	XM_047417105.1	c.607+8T>G		splice_region_variant, intron_variant			XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.559+8T>G		splice_region_variant, intron_variant		1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.559+8T>G		splice_region_variant, intron_variant		1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*317+8T>G		splice_region_variant, intron_variant		1		ENSP00000430595.1
GLRA1	ENST00000471351.2	n.842+8T>G		splice_region_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2623 AN: 152124 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00422 AC: 1061 AN: 251428 Hom.: 32 AF XY: 0.00305 AC XY: 414 AN XY: 135880

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00171 AC: 2472 AN: 1441426 Hom.: 77 Cov.: 27 AF XY: 0.00148 AC XY: 1060 AN XY: 718410

Gnomad4 AFR exome AF: 0.0613

Gnomad4 AMR exome AF: 0.00316

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000329

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.0173 AC: 2632 AN: 152242 Hom.: 88 Cov.: 33 AF XY: 0.0162 AC XY: 1208 AN XY: 74444

Gnomad4 AFR AF: 0.0591

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.00861 Hom.: 18

Bravo AF: 0.0198

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GLRA1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

- -

Hereditary hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000097
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs73285947; hg19: chr5-151235854;