rs75463357

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 352310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000171.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	NM_000171.4	MANE Select	c.1041G>A	p.Arg347Arg	synonymous	Exon 8 of 9	NP_000162.2
	GLRA1	NM_001146040.2		c.1041G>A	p.Arg347Arg	synonymous	Exon 8 of 9	NP_001139512.1
	GLRA1	NM_001292000.2		c.792G>A	p.Arg264Arg	synonymous	Exon 7 of 8	NP_001278929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.1041G>A	p.Arg347Arg	synonymous	Exon 8 of 9	ENSP00000274576.5
	GLRA1	ENST00000455880.2	TSL:1	c.1041G>A	p.Arg347Arg	synonymous	Exon 8 of 9	ENSP00000411593.2
	GLRA1	ENST00000462581.6	TSL:1	n.*799G>A		non_coding_transcript_exon	Exon 7 of 8	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

GnomAD2 exomes AF: 0.0162 AC: 4076 AN: 251118 AF XY: 0.0166

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 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

African (AFR) AF: 0.00293 AC: 98 AN: 33476

American (AMR) AF: 0.0121 AC: 541 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 527 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00400 AC: 345 AN: 86232

European-Finnish (FIN) AF: 0.0172 AC: 918 AN: 53400

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5766

European-Non Finnish (NFE) AF: 0.0239 AC: 26556 AN: 1111824

Other (OTH) AF: 0.0190 AC: 1146 AN: 60380

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

African (AFR) AF: 0.00440 AC: 183 AN: 41564

American (AMR) AF: 0.0144 AC: 221 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4824

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1598 AN: 68036

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0219 Hom.: 69

Bravo AF: 0.0154

Asia WGS AF: 0.00260 AC: 11 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0252

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary hyperekplexia (1)
-	-	1	Hyperekplexia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.5
DANN	Benign	0.67
PhyloP100		2.5
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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