rs281864920

Positions:

• chr5-151851410-A-C
• chr5-151851410-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The ENST00000274576.9(GLRA1):​c.892T>G​(p.Ser298Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S298T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLRA1 ENST00000274576.9 missense
• Clinical Significance: Not reported in ClinVar
• 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 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000274576.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.892T>G	p.Ser298Ala	missense_variant	7/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.892T>G	p.Ser298Ala	missense_variant	7/9		NP_001139512.1
GLRA1	NM_001292000.2	c.643T>G	p.Ser215Ala	missense_variant	6/8		NP_001278929.1
GLRA1	XM_047417105.1	c.940T>G	p.Ser314Ala	missense_variant	7/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.892T>G	p.Ser298Ala	missense_variant	7/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.892T>G	p.Ser298Ala	missense_variant	7/9	1		ENSP00000411593	A1
GLRA1	ENST00000471351.2	n.1175T>G		non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*650T>G		3_prime_UTR_variant, NMD_transcript_variant	6/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461132 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.047	D
MutationAssessor	Benign	-0.040	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.90	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.46	T;T
Sift4G	Benign	0.78	T;T
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.58		Loss of glycosylation at S298 (P = 0.0294);Loss of glycosylation at S298 (P = 0.0294);
MVP		0.88
MPC		0.87
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.42
gMVP		0.87

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;