rs1554083817

Variant names:

• chr5-151855127-C-T
• rs1554083817
• NM_000171.4:c.610G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-151855127-C-T
• chr5-151855127-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000171.4(GLRA1):​c.610G>A​(p.Val204Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.70
• Publications: 0 publications found

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]

GLRA1 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000171.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	NM_000171.4	MANE Select	c.610G>A	p.Val204Met	missense	Exon 6 of 9	NP_000162.2	P23415-2
	GLRA1	NM_001146040.2		c.610G>A	p.Val204Met	missense	Exon 6 of 9	NP_001139512.1	P23415-1
	GLRA1	NM_001292000.2		c.361G>A	p.Val121Met	missense	Exon 5 of 8	NP_001278929.1	Q14C71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.610G>A	p.Val204Met	missense	Exon 6 of 9	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.610G>A	p.Val204Met	missense	Exon 6 of 9	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000462581.6	TSL:1	n.*368G>A		non_coding_transcript_exon	Exon 5 of 8	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727080

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111662

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary hyperekplexia (1)
-	1	-	Hyperekplexia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.55		Gain of catalytic residue at V204 (P = 0.1536)
MVP		0.83
MPC		2.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.73
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1554083817; hg19: chr5-151234688; COSMIC: COSV105099652; COSMIC: COSV105099652;