NM_000171.4:c.913-262A>G

Variant names:

• chr5-151829329-T-C
• rs7733241
• NM_000171.4:c.913-262A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000171.4(GLRA1):​c.913-262A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 152,034 control chromosomes in the GnomAD database, including 17,281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (17281 hom., cov: 32)
• Consequence: GLRA1 NM_000171.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.839
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-151829329-T-C is Benign according to our data. Variant chr5-151829329-T-C is described in ClinVar as [Benign]. Clinvar id is 1283942.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.913-262A>G		intron_variant	Intron 7 of 8	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.913-262A>G		intron_variant	Intron 7 of 8		NP_001139512.1
GLRA1	NM_001292000.2	c.664-262A>G		intron_variant	Intron 6 of 7		NP_001278929.1
GLRA1	XM_047417105.1	c.961-262A>G		intron_variant	Intron 7 of 8		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.913-262A>G		intron_variant	Intron 7 of 8	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.913-262A>G		intron_variant	Intron 7 of 8	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*671-262A>G		intron_variant	Intron 6 of 7	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70755 AN: 151916 Hom.: 17246 Cov.: 32

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.441

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

GnomAD4 genome AF: 0.466 AC: 70837 AN: 152034 Hom.: 17281 Cov.: 32 AF XY: 0.463 AC XY: 34408 AN XY: 74298

African (AFR) AF: 0.621 AC: 25746 AN: 41464

American (AMR) AF: 0.390 AC: 5954 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1268 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1654 AN: 5174

South Asian (SAS) AF: 0.465 AC: 2244 AN: 4822

European-Finnish (FIN) AF: 0.419 AC: 4424 AN: 10554

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28236 AN: 67974

Other (OTH) AF: 0.444 AC: 936 AN: 2108

Alfa AF: 0.446 Hom.: 5185

Bravo AF: 0.467

Asia WGS AF: 0.447 AC: 1551 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.78
PhyloP100		-0.84
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: rs7733241; hg19: chr5-151208890;