rs3744333

Positions:

• chr17-15239438-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000304.4(PMP22):​c.319+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,612,302 control chromosomes in the GnomAD database, including 6,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (484 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5905 hom.)
• Consequence: PMP22 NM_000304.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.519

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014778078).
• BP6: Variant 17-15239438-G-A is Benign according to our data. Variant chr17-15239438-G-A is described in ClinVar as [Benign]. Clinvar id is 633490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4	c.319+33C>T		intron_variant		ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.319+33C>T		intron_variant		1	NM_000304.4	ENSP00000308937	P1

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 9912 AN: 152118 Hom.: 484 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0824

Gnomad OTH AF: 0.0746

GnomAD3 exomes AF: 0.0847 AC: 21288 AN: 251458 Hom.: 1208 AF XY: 0.0898 AC XY: 12208 AN XY: 135914

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0428

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.0884

GnomAD4 exome AF: 0.0846 AC: 123526 AN: 1460066 Hom.: 5905 Cov.: 32 AF XY: 0.0867 AC XY: 63010 AN XY: 726424

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.0438

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0828

Gnomad4 OTH exome AF: 0.0851

GnomAD4 genome AF: 0.0651 AC: 9910 AN: 152236 Hom.: 484 Cov.: 33 AF XY: 0.0633 AC XY: 4709 AN XY: 74430

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.0553

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.0824

Gnomad4 OTH AF: 0.0734

Alfa AF: 0.0710 Hom.: 109

Bravo AF: 0.0639

TwinsUK AF: 0.0790 AC: 293

ALSPAC AF: 0.0856 AC: 330

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.0887 AC: 763

ExAC AF: 0.0842 AC: 10228

Asia WGS AF: 0.148 AC: 511 AN: 3478

EpiCase AF: 0.0845

EpiControl AF: 0.0855

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Charcot-Marie-Tooth disease, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jan 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.88
DANN	Benign	0.68
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0015	T
MutationTaster	Benign	1.0	P;P;P;P;P
Sift4G	Uncertain	0.043	D
Vest4		0.079
GERP RS		-2.2

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: rs3744333; hg19: chr17-15142755; COSMIC: COSV56603015;