5-151822683-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000171.4(GLRA1):c.1340A>G(p.His447Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H447N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.1340A>G	p.His447Arg	missense_variant	9/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.1364A>G	p.His455Arg	missense_variant	9/9
GLRA1	NM_001292000.2	c.1091A>G	p.His364Arg	missense_variant	8/8
GLRA1	XM_047417105.1	c.1388A>G	p.His463Arg	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.1340A>G	p.His447Arg	missense_variant	9/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.1364A>G	p.His455Arg	missense_variant	9/9	1		A1
GLRA1	ENST00000462581.6	c.*1098A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.1340A>G (p.H447R) alteration is located in exon 9 (coding exon 9) of the GLRA1 gene. This alteration results from a A to G substitution at nucleotide position 1340, causing the histidine (H) at amino acid position 447 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.11	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.76
MutPred		0.39		.;Gain of MoRF binding (P = 0.0051);
MVP		0.81
MPC		0.30
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.55
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-151202244;