chr19-40394272-T-TTCC

Position:

• chr19-40394272-T-TTCC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The ENST00000324001.8(PRX):​c.4079_4080insGGA​(p.Glu1360dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,605,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PRX ENST00000324001.8 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.16

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-40394272-T-TTCC is Benign according to our data. Variant chr19-40394272-T-TTCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 699561.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.4079_4080insGGA	p.Glu1360dup	inframe_insertion	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.4364_4365insGGA	p.Glu1455dup	inframe_insertion	7/7		NP_001398056.1
PRX	XM_017027047.2	c.3977_3978insGGA	p.Glu1326dup	inframe_insertion	4/4		XP_016882536.1
PRX	NM_020956.2	c.*4284_*4285insGGA		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.4079_4080insGGA	p.Glu1360dup	inframe_insertion	7/7	1	NM_181882.3	ENSP00000326018	A2

Frequencies

GnomAD3 genomes AF: 0.000370 AC: 56 AN: 151214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000432 AC: 63 AN: 145830 Hom.: 0 AF XY: 0.000397 AC XY: 31 AN XY: 78150

Gnomad AFR exome AF: 0.000919

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.000104

Gnomad SAS exome AF: 0.00215

Gnomad FIN exome AF: 0.000334

Gnomad NFE exome AF: 0.0000592

Gnomad OTH exome AF: 0.00129

GnomAD4 exome AF: 0.000126 AC: 183 AN: 1453796 Hom.: 0 Cov.: 29 AF XY: 0.000123 AC XY: 89 AN XY: 722798

Gnomad4 AFR exome AF: 0.000811

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.000715

Gnomad4 FIN exome AF: 0.0000944

Gnomad4 NFE exome AF: 0.0000443

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.000410 AC: 62 AN: 151330 Hom.: 0 Cov.: 32 AF XY: 0.000338 AC XY: 25 AN XY: 73928

Gnomad4 AFR AF: 0.000798

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000193

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2019

In-frame duplication in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

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: rs139624657; hg19: chr19-40900179;