rs744389

Variant names:

• chr19-40398695-G-A
• rs744389
• NM_181882.3:c.306C>T

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.306C>T​(p.Thr102Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,946 control chromosomes in the GnomAD database, including 25,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1514 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24019 hom.)
• Consequence: PRX NM_181882.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.250
• Publications: 16 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=-0.49).
• BP6: Variant 19-40398695-G-A is Benign according to our data. Variant chr19-40398695-G-A is described in ClinVar as Benign. ClinVar VariationId is 130051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 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.306C>T	p.Thr102Thr	synonymous	Exon 6 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.591C>T	p.Thr197Thr	synonymous	Exon 6 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.306C>T	p.Thr102Thr	synonymous	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.306C>T	p.Thr102Thr	synonymous	Exon 6 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.306C>T	p.Thr102Thr	synonymous	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000673881.1		c.-112C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	ENSP00000501070.1	Q9BXM0-3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19172 AN: 152106 Hom.: 1515 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0949

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.140 AC: 35121 AN: 250146 AF XY: 0.148

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.0716

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0308

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.175 AC: 255736 AN: 1461722 Hom.: 24019 Cov.: 36 AF XY: 0.175 AC XY: 127596 AN XY: 727186

African (AFR) AF: 0.0325 AC: 1087 AN: 33476

American (AMR) AF: 0.0747 AC: 3339 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 2562 AN: 26126

East Asian (EAS) AF: 0.0226 AC: 896 AN: 39694

South Asian (SAS) AF: 0.188 AC: 16179 AN: 86256

European-Finnish (FIN) AF: 0.144 AC: 7663 AN: 53372

Middle Eastern (MID) AF: 0.114 AC: 655 AN: 5768

European-Non Finnish (NFE) AF: 0.192 AC: 213693 AN: 1111930

Other (OTH) AF: 0.160 AC: 9662 AN: 60382

GnomAD4 genome AF: 0.126 AC: 19167 AN: 152224 Hom.: 1514 Cov.: 32 AF XY: 0.123 AC XY: 9147 AN XY: 74424

African (AFR) AF: 0.0412 AC: 1711 AN: 41552

American (AMR) AF: 0.0947 AC: 1448 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3472

East Asian (EAS) AF: 0.0351 AC: 182 AN: 5184

South Asian (SAS) AF: 0.189 AC: 910 AN: 4820

European-Finnish (FIN) AF: 0.138 AC: 1461 AN: 10608

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12626 AN: 67984

Other (OTH) AF: 0.121 AC: 256 AN: 2112

Alfa AF: 0.155 Hom.: 3273

Bravo AF: 0.116

Asia WGS AF: 0.0870 AC: 303 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.179

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.25
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	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: rs744389; hg19: chr19-40904602; COSMIC: COSV52532202;