rs149023945

Positions:

• chr5-151892378-C-G
• chr5-151892378-C-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.117G>C​(p.Ser39=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,946 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.44

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=-0.65).
• BP6: Variant 5-151892378-C-G is Benign according to our data. Variant chr5-151892378-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 352321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00166 (253/152228) while in subpopulation NFE AF= 0.00231 (157/68012). AF 95% confidence interval is 0.00201. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.117G>C	p.Ser39=	synonymous_variant	2/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.117G>C	p.Ser39=	synonymous_variant	2/9		NP_001139512.1
GLRA1	XM_047417105.1	c.165G>C	p.Ser55=	synonymous_variant	2/9		XP_047273061.1
GLRA1	NM_001292000.2	c.-65-5590G>C		intron_variant			NP_001278929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.117G>C	p.Ser39=	synonymous_variant	2/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.117G>C	p.Ser39=	synonymous_variant	2/9	1		ENSP00000411593	A1
GLRA1	ENST00000471351.2	n.400G>C		non_coding_transcript_exon_variant	2/8	1
GLRA1	ENST00000462581.6	c.57-5590G>C		intron_variant, NMD_transcript_variant		1		ENSP00000430595

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152110 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00148 AC: 373 AN: 251252 Hom.: 1 AF XY: 0.00162 AC XY: 220 AN XY: 135796

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00178 AC: 2601 AN: 1461718 Hom.: 2 Cov.: 31 AF XY: 0.00185 AC XY: 1344 AN XY: 727174

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.00431

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152228 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74416

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Hereditary hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.68
DANN	Benign	0.62

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: rs149023945; hg19: chr5-151271939;