19-40403756-C-G

Variant names:

• chr19-40403756-C-G
• rs751441856
• NM_181882.3:c.134G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181882.3(PRX):​c.134G>C​(p.Arg45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,586,792 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R45Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10
• 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), Ambry Genetics, Orphanet
• 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 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	NM_181882.3	MANE Select	c.134G>C	p.Arg45Pro	missense	Exon 5 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.419G>C	p.Arg140Pro	missense	Exon 5 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.134G>C	p.Arg45Pro	missense	Exon 5 of 6	NP_066007.1	Q9BXM0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.134G>C	p.Arg45Pro	missense	Exon 5 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.134G>C	p.Arg45Pro	missense	Exon 5 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.419G>C	p.Arg140Pro	missense	Exon 5 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434650 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711772

African (AFR) AF: 0.0000307 AC: 1 AN: 32594

American (AMR) AF: 0.00 AC: 0 AN: 41882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 37738

South Asian (SAS) AF: 0.00 AC: 0 AN: 82538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099832

Other (OTH) AF: 0.00 AC: 0 AN: 59260

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.66	P
Vest4		0.78
MutPred		0.47		Gain of disorder (P = 0.152)
MVP		0.69
MPC		0.74
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.087	Neutral
Varity_R		0.75
gMVP		0.85
Mutation Taster		=36/64	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: rs751441856; hg19: chr19-40909663;