chr5-151822710-T-C

Variant names:

• chr5-151822710-T-C
• NM_000171.4:c.1313A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000171.4(GLRA1):​c.1313A>G​(p.Tyr438Cys) 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 (★).

• 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
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

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.1313A>G	p.Tyr438Cys	missense	Exon 9 of 9	NP_000162.2	P23415-2
	GLRA1	NM_001146040.2		c.1337A>G	p.Tyr446Cys	missense	Exon 9 of 9	NP_001139512.1	P23415-1
	GLRA1	NM_001292000.2		c.1064A>G	p.Tyr355Cys	missense	Exon 8 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.1313A>G	p.Tyr438Cys	missense	Exon 9 of 9	ENSP00000274576.5	P23415-2
	GLRA1	ENST00000455880.2	TSL:1	c.1337A>G	p.Tyr446Cys	missense	Exon 9 of 9	ENSP00000411593.2	P23415-1
	GLRA1	ENST00000462581.6	TSL:1	n.*1071A>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.75		Loss of catalytic residue at I445 (P = 0.051)
MVP		0.96
MPC		0.36
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.95
Mutation Taster		=4/96	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

hg19: chr5-151202271;