19-40397853-G-A

Position:

• chr19-40397853-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_181882.3(PRX):​c.499C>T​(p.Arg167Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,604,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.64

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03500694).
• BP6: Variant 19-40397853-G-A is Benign according to our data. Variant chr19-40397853-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448141.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.499C>T	p.Arg167Cys	missense_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.784C>T	p.Arg262Cys	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.397C>T	p.Arg133Cys	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*704C>T		3_prime_UTR_variant	6/6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.499C>T	p.Arg167Cys	missense_variant	7/7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000159 AC: 36 AN: 226454 Hom.: 0 AF XY: 0.0000728 AC XY: 9 AN XY: 123682

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000514

Gnomad NFE exome AF: 0.0000597

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1451714 Hom.: 1 Cov.: 35 AF XY: 0.0000915 AC XY: 66 AN XY: 721426

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.000164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.0000677

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74508

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000518

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The c.499C>T (p.R167C) alteration is located in exon 7 (coding exon 4) of the PRX gene. This alteration results from a C to T substitution at nucleotide position 499, causing the arginine (R) at amino acid position 167 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 09, 2018

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.14
Sift	Benign	0.041	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.45
MPC		0.85
ClinPred		0.044	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.60

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: rs10425452; hg19: chr19-40903760;