rs76960467

Variant names:

• chr19-40397071-G-A
• rs76960467
• NM_181882.3:c.1281C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-40397071-G-A
• chr19-40397071-G-C

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_001411127.1(PRX):​c.1566C>T​(p.Ile522Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,056 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (4 hom.)
• Consequence: PRX NM_001411127.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.90
• 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), Orphanet, Ambry Genetics
• 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=-0.91).
• BP6: Variant 19-40397071-G-A is Benign according to our data. Variant chr19-40397071-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00516 (786/152292) while in subpopulation AFR AF = 0.0182 (755/41566). AF 95% confidence interval is 0.0171. There are 8 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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_001411127.1. 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.1281C>T	p.Ile427Ile	synonymous	Exon 7 of 7	NP_870998.2
	PRX	NM_001411127.1		c.1566C>T	p.Ile522Ile	synonymous	Exon 7 of 7	NP_001398056.1
	PRX	NM_020956.2		c.*1486C>T		3_prime_UTR	Exon 6 of 6	NP_066007.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.1281C>T	p.Ile427Ile	synonymous	Exon 7 of 7	ENSP00000326018.6
	PRX	ENST00000291825.11	TSL:1	c.*1486C>T		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6
	PRX	ENST00000674005.2		c.1566C>T	p.Ile522Ile	synonymous	Exon 7 of 7	ENSP00000501261.1

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 786 AN: 152174 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00144 AC: 362 AN: 250950 AF XY: 0.00108

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000616 AC: 900 AN: 1461764 Hom.: 4 Cov.: 36 AF XY: 0.000540 AC XY: 393 AN XY: 727196

African (AFR) AF: 0.0175 AC: 587 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000145 AC: 161 AN: 1112006

Other (OTH) AF: 0.00129 AC: 78 AN: 60396

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152292 Hom.: 8 Cov.: 33 AF XY: 0.00495 AC XY: 369 AN XY: 74474

African (AFR) AF: 0.0182 AC: 755 AN: 41566

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00236 Hom.: 1

Bravo AF: 0.00591

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4F (1)
-	-	1	Dejerine-Sottas disease;C3540453:Charcot-Marie-Tooth disease type 4F (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.66
PhyloP100		-4.9
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: rs76960467; hg19: chr19-40902978; COSMIC: COSV107341999;