rs139950446

Variant names:

• chr19-40394650-G-A
• rs139950446
• NM_181882.3:c.3702C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_181882.3(PRX):​c.3702C>T​(p.Gly1234Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,607,154 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (39 hom.)
• Consequence: PRX NM_181882.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -7.27
• 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=-0.96).
• BP6: Variant 19-40394650-G-A is Benign according to our data. Variant chr19-40394650-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00328 (499/151992) while in subpopulation EAS AF = 0.0333 (171/5138). AF 95% confidence interval is 0.0292. There are 8 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR 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.3702C>T	p.Gly1234Gly	synonymous	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.3987C>T	p.Gly1329Gly	synonymous	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*3907C>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.3702C>T	p.Gly1234Gly	synonymous	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*3907C>T		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.3987C>T	p.Gly1329Gly	synonymous	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 499 AN: 151874 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.00313

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00483 AC: 1174 AN: 243202 AF XY: 0.00444

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0300

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00515

GnomAD4 exome AF: 0.00215 AC: 3130 AN: 1455162 Hom.: 39 Cov.: 33 AF XY: 0.00205 AC XY: 1486 AN XY: 724210

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000716 AC: 32 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26114

East Asian (EAS) AF: 0.0289 AC: 1146 AN: 39698

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86246

European-Finnish (FIN) AF: 0.0259 AC: 1215 AN: 47000

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000295 AC: 328 AN: 1111804

Other (OTH) AF: 0.00456 AC: 275 AN: 60340

GnomAD4 genome AF: 0.00328 AC: 499 AN: 151992 Hom.: 8 Cov.: 32 AF XY: 0.00437 AC XY: 325 AN XY: 74292

African (AFR) AF: 0.000121 AC: 5 AN: 41448

American (AMR) AF: 0.000720 AC: 11 AN: 15278

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

East Asian (EAS) AF: 0.0333 AC: 171 AN: 5138

South Asian (SAS) AF: 0.00313 AC: 15 AN: 4796

European-Finnish (FIN) AF: 0.0215 AC: 228 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000854 AC: 58 AN: 67950

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00261 Hom.: 2

Bravo AF: 0.00170

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.093
DANN	Benign	0.58
PhyloP100		-7.3
Mutation Taster		=100/0	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: rs139950446; hg19: chr19-40900557; COSMIC: COSV52525005; COSMIC: COSV52525005;