rs4803335

Variant names:

• chr19-40397881-C-T
• rs4803335
• NM_181882.3:c.471G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181882.3(PRX):​c.471G>A​(p.Glu157Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,610,576 control chromosomes in the GnomAD database, including 1,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (128 hom., cov: 33)
  • Exomes 𝑓: 0.011 (1081 hom.)
• Consequence: PRX NM_181882.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.13
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-40397881-C-T is Benign according to our data. Variant chr19-40397881-C-T is described in ClinVar as Benign. ClinVar VariationId is 329288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 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.471G>A	p.Glu157Glu	synonymous	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.756G>A	p.Glu252Glu	synonymous	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*676G>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.471G>A	p.Glu157Glu	synonymous	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*676G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.756G>A	p.Glu252Glu	synonymous	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2321 AN: 152220 Hom.: 126 Cov.: 33

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0337 AC: 8100 AN: 240040 AF XY: 0.0264

Gnomad AFR exome AF: 0.00374

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0107 AC: 15627 AN: 1458238 Hom.: 1081 Cov.: 35 AF XY: 0.00997 AC XY: 7230 AN XY: 725260

African (AFR) AF: 0.00296 AC: 99 AN: 33462

American (AMR) AF: 0.203 AC: 8914 AN: 43888

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26002

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39640

South Asian (SAS) AF: 0.00986 AC: 845 AN: 85662

European-Finnish (FIN) AF: 0.00323 AC: 171 AN: 52940

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5764

European-Non Finnish (NFE) AF: 0.00443 AC: 4922 AN: 1110698

Other (OTH) AF: 0.0107 AC: 643 AN: 60182

GnomAD4 genome AF: 0.0153 AC: 2328 AN: 152338 Hom.: 128 Cov.: 33 AF XY: 0.0171 AC XY: 1275 AN XY: 74488

African (AFR) AF: 0.00440 AC: 183 AN: 41596

American (AMR) AF: 0.113 AC: 1732 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4828

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68026

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.00739 Hom.: 19

Bravo AF: 0.0272

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4803335; hg19: chr19-40903788;