chr17-15230340-A-G

Variant names:

• chr17-15230340-A-G
• rs7538
• NM_000304.4:c.*577T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000304.4(PMP22):​c.*577T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 155,022 control chromosomes in the GnomAD database, including 4,218 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (4122 hom., cov: 33)
  • Exomes 𝑓: 0.23 (96 hom.)
• Consequence: PMP22 NM_000304.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.66
• Publications: 13 publications found

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]

PMP22 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 1E

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.*577T>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.*577T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31038 AN: 151992 Hom.: 4121 Cov.: 33

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.228 AC: 664 AN: 2912 Hom.: 96 Cov.: 0 AF XY: 0.228 AC XY: 358 AN XY: 1572

African (AFR) AF: 0.00 AC: 0 AN: 8

American (AMR) AF: 0.160 AC: 93 AN: 582

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 1 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 60

South Asian (SAS) AF: 0.180 AC: 31 AN: 172

European-Finnish (FIN) AF: 0.326 AC: 141 AN: 432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.240 AC: 378 AN: 1572

Other (OTH) AF: 0.256 AC: 20 AN: 78

GnomAD4 genome AF: 0.204 AC: 31041 AN: 152110 Hom.: 4122 Cov.: 33 AF XY: 0.204 AC XY: 15146 AN XY: 74374

African (AFR) AF: 0.0597 AC: 2480 AN: 41526

American (AMR) AF: 0.205 AC: 3134 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3470

East Asian (EAS) AF: 0.00929 AC: 48 AN: 5168

South Asian (SAS) AF: 0.198 AC: 956 AN: 4826

European-Finnish (FIN) AF: 0.314 AC: 3320 AN: 10558

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 19967 AN: 67980

Other (OTH) AF: 0.205 AC: 433 AN: 2112

Alfa AF: 0.251 Hom.: 7072

Bravo AF: 0.187

Asia WGS AF: 0.0980 AC: 345 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary liability to pressure palsies Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.22
DANN	Benign	0.66
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7538; hg19: chr17-15133657; COSMIC: COSV56602193; COSMIC: COSV56602193;