5-151829060-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000171.4(GLRA1):c.920A>C(p.Tyr307Ser) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y307C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-151829060-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 5-151829060-T-G is Pathogenic according to our data. Variant chr5-151829060-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 38334.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.920A>C	p.Tyr307Ser	missense_variant	8/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.920A>C	p.Tyr307Ser	missense_variant	8/9
GLRA1	NM_001292000.2	c.671A>C	p.Tyr224Ser	missense_variant	7/8
GLRA1	XM_047417105.1	c.968A>C	p.Tyr323Ser	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.920A>C	p.Tyr307Ser	missense_variant	8/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.920A>C	p.Tyr307Ser	missense_variant	8/9	1		A1
GLRA1	ENST00000462581.6	c.*678A>C		3_prime_UTR_variant, NMD_transcript_variant	7/8	1

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

Pathogenic, no assertion criteria provided

curation

GeneReviews

Oct 04, 2012

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.45	P;P
Vest4		0.92
MutPred		0.91		Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);
MVP		0.90
MPC		0.38
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98

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: rs121918410; hg19: chr5-151208621;