19-40396774-C-T

Position:

• chr19-40396774-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The ENST00000324001.8(PRX):​c.1578G>A​(p.Ser526=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRX ENST00000324001.8 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -11.0

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-40396774-C-T is Benign according to our data. Variant chr19-40396774-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 543446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-11 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.1578G>A	p.Ser526=	synonymous_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.1863G>A	p.Ser621=	synonymous_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.1476G>A	p.Ser492=	synonymous_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*1783G>A		3_prime_UTR_variant	6/6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.1578G>A	p.Ser526=	synonymous_variant	7/7	1	NM_181882.3	ENSP00000326018	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 20 AN: 102214 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.000114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000522

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000318

Gnomad FIN AF: 0.000173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000183

Gnomad OTH AF: 0.000718

GnomAD3 exomes AF: 0.0000228 AC: 5 AN: 219134 Hom.: 0 AF XY: 0.00000834 AC XY: 1 AN XY: 119900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000361 AC: 50 AN: 1384852 Hom.: 0 Cov.: 37 AF XY: 0.0000363 AC XY: 25 AN XY: 687920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000378

Gnomad4 ASJ exome AF: 0.0000426

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000281

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000196 AC: 20 AN: 102264 Hom.: 0 Cov.: 30 AF XY: 0.000141 AC XY: 7 AN XY: 49554

Gnomad4 AFR AF: 0.000114

Gnomad4 AMR AF: 0.000521

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000319

Gnomad4 FIN AF: 0.000173

Gnomad4 NFE AF: 0.000183

Gnomad4 OTH AF: 0.000712

Alfa AF: 0.00455 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

PRX-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs567690884; hg19: chr19-40902681; COSMIC: COSV52528493;