19-40397136-C-T

Position:

• chr19-40397136-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181882.3(PRX):​c.1216G>A​(p.Ala406Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,614,152 control chromosomes in the GnomAD database, including 54 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (45 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.733

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 (MetaRNN=0.0028489232).
• BP6: Variant 19-40397136-C-T is Benign according to our data. Variant chr19-40397136-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220724.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}. Variant chr19-40397136-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00445 (678/152330) while in subpopulation NFE AF= 0.00612 (416/68024). AF 95% confidence interval is 0.00563. There are 9 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.1216G>A	p.Ala406Thr	missense_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.1501G>A	p.Ala501Thr	missense_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.1114G>A	p.Ala372Thr	missense_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*1421G>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.1216G>A	p.Ala406Thr	missense_variant	7/7	1	NM_181882.3	ENSP00000326018	A2

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 678 AN: 152212 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00451 AC: 1131 AN: 250982 Hom.: 4 AF XY: 0.00457 AC XY: 621 AN XY: 135828

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00785

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.00564

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00557 AC: 8136 AN: 1461822 Hom.: 45 Cov.: 36 AF XY: 0.00556 AC XY: 4046 AN XY: 727220

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00614

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00445 AC: 678 AN: 152330 Hom.: 9 Cov.: 33 AF XY: 0.00446 AC XY: 332 AN XY: 74488

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.00612

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00586 Hom.: 5

Bravo AF: 0.00314

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00453 AC: 550

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PRX: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2023	- -

Charcot-Marie-Tooth disease type 4F Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.20
DANN	Benign	0.63
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	0.92	D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.042
Sift	Benign	0.23	T
Sift4G	Benign	0.10	T
Polyphen		0.0070	B
Vest4		0.13
MVP		0.085
MPC		0.22
ClinPred		0.0021	T
GERP RS		-3.2
Varity_R		0.035
gMVP		0.075

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: rs117336941; hg19: chr19-40903043;