rs771234852

chr19-40394105-G-GACA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_181882.3(PRX):c.4246_4247insTGT(p.Val1415_Ser1416insLeu) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,609,186 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: PRX NM_181882.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.131

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_181882.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRX	NM_181882.3	c.4246_4247insTGT	p.Val1415_Ser1416insLeu	inframe_insertion	7/7	ENST00000324001.8
PRX	NM_001411127.1	c.4531_4532insTGT	p.Val1510_Ser1511insLeu	inframe_insertion	7/7
PRX	XM_017027047.2	c.4144_4145insTGT	p.Val1381_Ser1382insLeu	inframe_insertion	4/4
PRX	NM_020956.2	c.*4451_*4452insTGT		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRX	ENST00000324001.8	c.4246_4247insTGT	p.Val1415_Ser1416insLeu	inframe_insertion	7/7	1	NM_181882.3	A2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000213 AC: 53 AN: 249318 Hom.: 0 AF XY: 0.000297 AC XY: 40 AN XY: 134774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1457044 Hom.: 1 Cov.: 30 AF XY: 0.000178 AC XY: 129 AN XY: 723972

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: 0.00138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000505

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2020	In-frame insertion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2020

The c.4244_4246dupTGT variant (also known as p.V1415_S1416insL), located in coding exon 4 of the PRX gene, results from an in-frame insertion of TGT due to the duplication of nucleotides 4244 through 4246. This results in the insertion of an extra residue (L) between codon 1415 and codon 1416. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771234852; hg19: chr19-40900012;