rs1465555

Variant names:

• chr5-151910137-T-C
• rs1465555
• NM_000171.4:c.56+14357A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000171.4(GLRA1):​c.56+14357A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 152,038 control chromosomes in the GnomAD database, including 40,872 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (40872 hom., cov: 31)
• Consequence: GLRA1 NM_000171.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.571
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	NM_000171.4	MANE Select	c.56+14357A>G		intron	N/A	NP_000162.2	P23415-2
	GLRA1	NM_001146040.2		c.56+14357A>G		intron	N/A	NP_001139512.1	P23415-1
	GLRA1	NM_001292000.2		c.-66+14357A>G		intron	N/A	NP_001278929.1	Q14C71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.56+14357A>G		intron	N/A	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.56+14357A>G		intron	N/A	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000462581.6	TSL:1	n.56+14357A>G		intron	N/A	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110370 AN: 151920 Hom.: 40815 Cov.: 31

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.704

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.727 AC: 110485 AN: 152038 Hom.: 40872 Cov.: 31 AF XY: 0.723 AC XY: 53724 AN XY: 74320

African (AFR) AF: 0.877 AC: 36407 AN: 41504

American (AMR) AF: 0.704 AC: 10763 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2406 AN: 3468

East Asian (EAS) AF: 0.676 AC: 3483 AN: 5152

South Asian (SAS) AF: 0.612 AC: 2937 AN: 4800

European-Finnish (FIN) AF: 0.616 AC: 6501 AN: 10556

Middle Eastern (MID) AF: 0.695 AC: 203 AN: 292

European-Non Finnish (NFE) AF: 0.672 AC: 45657 AN: 67970

Other (OTH) AF: 0.704 AC: 1487 AN: 2112

Alfa AF: 0.690 Hom.: 133118

Bravo AF: 0.742

Asia WGS AF: 0.665 AC: 2314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.3
DANN	Benign	0.73
PhyloP100		-0.57
Mutation Taster		=100/0	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: rs1465555; hg19: chr5-151289698; COSMIC: COSV51009003;