rs201337455

Variant names:

• chr19-40396728-G-A
• rs201337455
• NM_181882.3:c.1624C>T
• PRX p.Arg542Trp

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181882.3(PRX):​c.1624C>T​(p.Arg542Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,612,864 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R542Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (9 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.807
• 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: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011014193).
• BP6: Variant 19-40396728-G-A is Benign according to our data. Variant chr19-40396728-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 416226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000381 (58/152038) while in subpopulation SAS AF = 0.00707 (34/4808). AF 95% confidence interval is 0.0052. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.1624C>T	p.Arg542Trp	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.1909C>T	p.Arg637Trp	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*1829C>T		3_prime_UTR	Exon 6 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.1624C>T	p.Arg542Trp	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*1829C>T		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.1909C>T	p.Arg637Trp	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 151924 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000360 AC: 90 AN: 249778 AF XY: 0.000414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000880

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1460826 Hom.: 9 Cov.: 37 AF XY: 0.000486 AC XY: 353 AN XY: 726632

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.00417 AC: 358 AN: 85780

European-Finnish (FIN) AF: 0.00229 AC: 122 AN: 53380

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111904

Other (OTH) AF: 0.000331 AC: 20 AN: 60338

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152038 Hom.: 0 Cov.: 33 AF XY: 0.000673 AC XY: 50 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00707 AC: 34 AN: 4808

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.0000935 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4F (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.81
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.020	D
Varity_R		0.055
gMVP		0.26
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201337455;

hg19: chr19-40902635;