5-151828987-G-T

Variant names:

• chr5-151828987-G-T
• rs17112272
• NM_000171.4:c.993C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000171.4(GLRA1):​c.993C>A​(p.Ala331Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A331A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.942
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.942 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.993C>A	p.Ala331Ala	synonymous_variant	Exon 8 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.993C>A	p.Ala331Ala	synonymous_variant	Exon 8 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.744C>A	p.Ala248Ala	synonymous_variant	Exon 7 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.1041C>A	p.Ala347Ala	synonymous_variant	Exon 8 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.993C>A	p.Ala331Ala	synonymous_variant	Exon 8 of 9	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.993C>A	p.Ala331Ala	synonymous_variant	Exon 8 of 9	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*751C>A		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000430595.1
GLRA1	ENST00000462581.6	n.*751C>A		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.31
DANN	Benign	0.68
PhyloP100		-0.94

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: rs17112272; hg19: chr5-151208548;