rs200835105

Variant names:

• chr19-40394222-C-T
• rs200835105
• NM_181882.3:c.4130G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181882.3(PRX):​c.4130G>A​(p.Arg1377His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,599,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R1377C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.28
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13967776).

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.4130G>A	p.Arg1377His	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.4415G>A	p.Arg1472His	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*4335G>A		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.4130G>A	p.Arg1377His	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*4335G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.4415G>A	p.Arg1472His	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000373 AC: 9 AN: 241384 AF XY: 0.0000535

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000318 AC: 46 AN: 1447002 Hom.: 0 Cov.: 30 AF XY: 0.0000293 AC XY: 21 AN XY: 717378

African (AFR) AF: 0.000452 AC: 15 AN: 33168

American (AMR) AF: 0.0000228 AC: 1 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25396

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.0000353 AC: 3 AN: 84958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000227 AC: 25 AN: 1101936

Other (OTH) AF: 0.0000335 AC: 2 AN: 59630

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74422

African (AFR) AF: 0.000120 AC: 5 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000385 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.093
Sift	Benign	0.084	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.53
MPC		0.71
ClinPred		0.19	T
GERP RS		2.7
Varity_R		0.065
gMVP		0.56
Mutation Taster		=88/12	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: rs200835105; hg19: chr19-40900129;