5-151856324-G-T

Variant names:

• chr5-151856324-G-T
• rs372452903
• NM_000171.4:c.536C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000171.4(GLRA1):​c.536C>A​(p.Thr179Lys) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T179I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.88
• 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: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

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.536C>A	p.Thr179Lys	missense	Exon 5 of 9	NP_000162.2
	GLRA1	NM_001146040.2		c.536C>A	p.Thr179Lys	missense	Exon 5 of 9	NP_001139512.1
	GLRA1	NM_001292000.2		c.287C>A	p.Thr96Lys	missense	Exon 4 of 8	NP_001278929.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA1	ENST00000274576.9	TSL:1 MANE Select	c.536C>A	p.Thr179Lys	missense	Exon 5 of 9	ENSP00000274576.5
	GLRA1	ENST00000455880.2	TSL:1	c.536C>A	p.Thr179Lys	missense	Exon 5 of 9	ENSP00000411593.2
	GLRA1	ENST00000462581.6	TSL:1	n.*294C>A		non_coding_transcript_exon	Exon 4 of 8	ENSP00000430595.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	GLRA1-related disorder (1)
-	1	-	Hereditary hyperekplexia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Benign	0.96
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.73
Sift	Benign	0.073	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.55		Gain of methylation at T179 (P = 0.0014)
MVP		0.92
MPC		1.6
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.65
gMVP		0.77
Mutation Taster		=22/78	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: rs372452903; hg19: chr5-151235885;