19-40403816-G-T

Position:

• chr19-40403816-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000324001.8(PRX):​c.74C>A​(p.Ala25Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A25A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRX ENST00000324001.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.87

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.74C>A	p.Ala25Glu	missense_variant	5/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.359C>A	p.Ala120Glu	missense_variant	5/7		NP_001398056.1
PRX	NM_020956.2	c.74C>A	p.Ala25Glu	missense_variant	5/6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.74C>A	p.Ala25Glu	missense_variant	5/7	1	NM_181882.3	ENSP00000326018	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 01, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a PRX-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 25 of the PRX protein (p.Ala25Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. In summary, this variant has uncertain impact on PRX function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D;N
REVEL	Uncertain	0.36
Sift	Benign	0.44	T;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.58
MutPred		0.24		Gain of disorder (P = 0.0341);Gain of disorder (P = 0.0341);
MVP		0.63
MPC		0.79
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.73

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: rs1555802182; hg19: chr19-40909723;