rs1554086308

Positions:

• chr5-151892410-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000171.4(GLRA1):​c.85G>T​(p.Ala29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21804115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.85G>T	p.Ala29Ser	missense_variant	2/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.85G>T	p.Ala29Ser	missense_variant	2/9		NP_001139512.1
GLRA1	XM_047417105.1	c.133G>T	p.Ala45Ser	missense_variant	2/9		XP_047273061.1
GLRA1	NM_001292000.2	c.-65-5622G>T		intron_variant			NP_001278929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.85G>T	p.Ala29Ser	missense_variant	2/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.85G>T	p.Ala29Ser	missense_variant	2/9	1		ENSP00000411593	A1
GLRA1	ENST00000471351.2	n.368G>T		non_coding_transcript_exon_variant	2/8	1
GLRA1	ENST00000462581.6	c.57-5622G>T		intron_variant, NMD_transcript_variant		1		ENSP00000430595

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hyperekplexia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLRA1 protein function. ClinVar contains an entry for this variant (Variation ID: 464193). This variant has not been reported in the literature in individuals affected with GLRA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 29 of the GLRA1 protein (p.Ala29Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.13
Sift	Benign	0.44	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.89	P;P
Vest4		0.25
MutPred		0.27		Gain of phosphorylation at A29 (P = 0.0073);Gain of phosphorylation at A29 (P = 0.0073);
MVP		0.78
MPC		1.5
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.36

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: rs1554086308; hg19: chr5-151271971;