rs1049349860

chr19-40397211-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181882.3(PRX):c.1141A>C(p.Ser381Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.160

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2127082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.1141A>C	p.Ser381Arg	missense_variant	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.1426A>C	p.Ser476Arg	missense_variant	7/7
PRX	XM_017027047.2	c.1039A>C	p.Ser347Arg	missense_variant	4/4
PRX	NM_020956.2	c.*1346A>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.1141A>C	p.Ser381Arg	missense_variant	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461696 Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 381 of the PRX protein (p.Ser381Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 476948). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.072
Sift	Benign	0.50	T
Sift4G	Benign	0.20	T
Polyphen		0.69	P
Vest4		0.38
MutPred		0.21		Gain of methylation at S381 (P = 0.0168);
MVP		0.40
MPC		0.26
ClinPred		0.69	D
GERP RS		4.4
Varity_R		0.11
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: rs1049349860; hg19: chr19-40903118;