rs73933276

chr19-40397301-G-Achr19-40397301-G-C

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.1051C>T(p.Pro351Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0037 in 1,613,266 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (89 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.78

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=0.005027175).
• BP6: Variant 19-40397301-G-A is Benign according to our data. Variant chr19-40397301-G-A is described in ClinVar as [Benign]. Clinvar id is 220690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40397301-G-A is described in Lovd as [Benign]. Variant chr19-40397301-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.1051C>T	p.Pro351Ser	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.1336C>T	p.Pro446Ser	missense_variant	7/7
PRX	XM_017027047.2	c.949C>T	p.Pro317Ser	missense_variant	4/4
PRX	NM_020956.2	c.*1256C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.1051C>T	p.Pro351Ser	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2893 AN: 152124 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00507 AC: 1254 AN: 247290 Hom.: 35 AF XY: 0.00377 AC XY: 507 AN XY: 134656

Gnomad AFR exome AF: 0.0672

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00210 AC: 3070 AN: 1461024 Hom.: 89 Cov.: 35 AF XY: 0.00183 AC XY: 1331 AN XY: 726818

Gnomad4 AFR exome AF: 0.0674

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.0190 AC: 2896 AN: 152242 Hom.: 94 Cov.: 33 AF XY: 0.0183 AC XY: 1364 AN XY: 74456

Gnomad4 AFR AF: 0.0663

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00861 Hom.: 17

Bravo AF: 0.0223

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0655 AC: 288

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00634 AC: 769

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

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 4F Benign:1

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. -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.64
MPC		0.69
ClinPred		0.058	T
GERP RS		4.6
Varity_R		0.40
gMVP		0.28

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: rs73933276; hg19: chr19-40903208;