19-40395707-A-G

Position:

• chr19-40395707-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181882.3(PRX):​c.2645T>C​(p.Val882Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,456 control chromosomes in the GnomAD database, including 229,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V882G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.58 (27096 hom., cov: 33)
  • Exomes 𝑓: 0.52 (202880 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.561

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.21127E-7).
• BP6: Variant 19-40395707-A-G is Benign according to our data. Variant chr19-40395707-A-G is described in ClinVar as [Benign]. Clinvar id is 130048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40395707-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.2645T>C	p.Val882Ala	missense_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.2930T>C	p.Val977Ala	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.2543T>C	p.Val848Ala	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*2850T>C		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.2645T>C	p.Val882Ala	missense_variant	7/7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87645 AN: 151538 Hom.: 27054 Cov.: 33

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.550

GnomAD3 exomes AF: 0.500 AC: 125436 AN: 250946 Hom.: 33041 AF XY: 0.495 AC XY: 67146 AN XY: 135728

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.474

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.521 AC: 761420 AN: 1461798 Hom.: 202880 Cov.: 97 AF XY: 0.518 AC XY: 376955 AN XY: 727192

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.472

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.578 AC: 87734 AN: 151658 Hom.: 27096 Cov.: 33 AF XY: 0.569 AC XY: 42154 AN XY: 74116

Gnomad4 AFR AF: 0.800

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.543

Alfa AF: 0.540 Hom.: 10153

Bravo AF: 0.596

TwinsUK AF: 0.536 AC: 1987

ALSPAC AF: 0.533 AC: 2055

ESP6500AA AF: 0.789 AC: 3477

ESP6500EA AF: 0.518 AC: 4453

ExAC AF: 0.507 AC: 61551

Asia WGS AF: 0.337 AC: 1174 AN: 3478

EpiCase AF: 0.509

EpiControl AF: 0.522

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Charcot-Marie-Tooth disease type 4F Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Dejerine-Sottas disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.42
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00075	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.046
Sift	Benign	0.38	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.27
ClinPred		0.0091	T
GERP RS		2.7
Varity_R		0.018
gMVP		0.096

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: rs268671; hg19: chr19-40901614; COSMIC: COSV52530169;