NM_181882.3:c.3248C>G

Variant names:

• chr19-40395104-G-C
• rs3745202
• NM_181882.3:c.3248C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181882.3(PRX):​c.3248C>G​(p.Pro1083Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,640 control chromosomes in the GnomAD database, including 24,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1083L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1480 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23458 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.76
• Publications: 30 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014650226).
• BP6: Variant 19-40395104-G-C is Benign according to our data. Variant chr19-40395104-G-C is described in ClinVar as Benign. ClinVar VariationId is 130052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

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.3248C>G	p.Pro1083Arg	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.3533C>G	p.Pro1178Arg	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*3453C>G		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.3248C>G	p.Pro1083Arg	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*3453C>G		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.3533C>G	p.Pro1178Arg	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18906 AN: 151950 Hom.: 1481 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0917

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.137 AC: 34384 AN: 251006 AF XY: 0.144

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0307

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.173 AC: 252568 AN: 1461572 Hom.: 23458 Cov.: 97 AF XY: 0.173 AC XY: 125616 AN XY: 727126

African (AFR) AF: 0.0323 AC: 1082 AN: 33478

American (AMR) AF: 0.0730 AC: 3265 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 2555 AN: 26136

East Asian (EAS) AF: 0.0224 AC: 891 AN: 39700

South Asian (SAS) AF: 0.168 AC: 14464 AN: 86258

European-Finnish (FIN) AF: 0.144 AC: 7627 AN: 53138

Middle Eastern (MID) AF: 0.107 AC: 618 AN: 5768

European-Non Finnish (NFE) AF: 0.191 AC: 212509 AN: 1111984

Other (OTH) AF: 0.158 AC: 9557 AN: 60388

GnomAD4 genome AF: 0.124 AC: 18901 AN: 152068 Hom.: 1480 Cov.: 32 AF XY: 0.121 AC XY: 8999 AN XY: 74326

African (AFR) AF: 0.0410 AC: 1702 AN: 41496

American (AMR) AF: 0.0916 AC: 1398 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3470

East Asian (EAS) AF: 0.0347 AC: 179 AN: 5164

South Asian (SAS) AF: 0.172 AC: 828 AN: 4814

European-Finnish (FIN) AF: 0.138 AC: 1455 AN: 10576

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12517 AN: 67962

Other (OTH) AF: 0.119 AC: 252 AN: 2110

Alfa AF: 0.152 Hom.: 1530

Bravo AF: 0.115

TwinsUK AF: 0.201 AC: 745

ALSPAC AF: 0.199 AC: 768

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.179 AC: 1542

ExAC AF: 0.141 AC: 17101

Asia WGS AF: 0.0810 AC: 281 AN: 3478

EpiCase AF: 0.170

EpiControl AF: 0.177

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Charcot-Marie-Tooth disease type 4F (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.064
Sift	Benign	0.11	T
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.11
MPC		0.82
ClinPred		0.024	T
GERP RS		1.3
Varity_R		0.049
gMVP		0.075
Mutation Taster		=97/3	polymorphism (auto)

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: rs3745202; hg19: chr19-40901011; COSMIC: COSV104390974; COSMIC: COSV104390974;