5-151851410-A-T

Variant names:

• chr5-151851410-A-T
• rs281864920
• NM_000171.4:c.892T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000171.4(GLRA1):​c.892T>A​(p.Ser298Thr) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.11

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical; Name=2 (size 20) in uniprot entity GLRA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant 5-151851410-A-T is Pathogenic according to our data. Variant chr5-151851410-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 38333.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-151851410-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.892T>A	p.Ser298Thr	missense_variant	Exon 7 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.892T>A	p.Ser298Thr	missense_variant	Exon 7 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.643T>A	p.Ser215Thr	missense_variant	Exon 6 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.940T>A	p.Ser314Thr	missense_variant	Exon 7 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.892T>A	p.Ser298Thr	missense_variant	Exon 7 of 9	1	NM_000171.4	ENSP00000274576.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1

Oct 04, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.54	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.35	T;T
Sift4G	Benign	0.90	T;T
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.74		Loss of disorder (P = 0.0752);Loss of disorder (P = 0.0752);
MVP		0.89
MPC		1.3
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.52
gMVP		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

Publications

LitVar

Other links and lift over

dbSNP: rs281864920; hg19: chr5-151230971;