19-40397843-A-G

Variant names:

• chr19-40397843-A-G
• rs1387520113
• NM_181882.3:c.509T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181882.3(PRX):​c.509T>C​(p.Leu170Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.984
• Publications: 0 publications found

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]

PRX Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4F

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29636914).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	NM_181882.3	MANE Select	c.509T>C	p.Leu170Pro	missense	Exon 7 of 7	NP_870998.2
	PRX	NM_001411127.1		c.794T>C	p.Leu265Pro	missense	Exon 7 of 7	NP_001398056.1
	PRX	NM_020956.2		c.*714T>C		3_prime_UTR	Exon 6 of 6	NP_066007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.509T>C	p.Leu170Pro	missense	Exon 7 of 7	ENSP00000326018.6
	PRX	ENST00000291825.11	TSL:1	c.*714T>C		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6
	PRX	ENST00000674005.2		c.794T>C	p.Leu265Pro	missense	Exon 7 of 7	ENSP00000501261.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448810 Hom.: 0 Cov.: 35 AF XY: 0.00000278 AC XY: 2 AN XY: 719630

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 41860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 84148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1106774

Other (OTH) AF: 0.00 AC: 0 AN: 59910

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.98
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.23	T
Polyphen		0.96	D
Vest4		0.47
MutPred		0.34		Loss of stability (P = 0.0164)
MVP		0.43
MPC		0.98
ClinPred		0.67	D
GERP RS		3.6
Varity_R		0.21
gMVP		0.48
Mutation Taster		=70/30	polymorphism

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: rs1387520113; hg19: chr19-40903750;