Genetic Variant PMP22:c.*544C>T (chr17-15230373-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000304.4(PMP22):c.*544C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 135,746 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: 𝑓 0.000074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMP22
NM_000304.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.583

Publications

0 publications found

Variant links:

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: Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
hereditary neuropathy with liability to pressure palsies
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 1E
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PMP22 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BS2

High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000304.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMP22	NM_000304.4	MANE Select	c.*544C>T	3_prime_UTR	Exon 5 of 5	NP_000295.1	Q01453
PMP22	NM_001281455.2		c.*544C>T	3_prime_UTR	Exon 5 of 5	NP_001268384.1	Q6FH25
PMP22	NM_001281456.2		c.*544C>T	3_prime_UTR	Exon 5 of 5	NP_001268385.1	Q01453

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMP22	ENST00000312280.9	TSL:1 MANE Select	c.*544C>T	3_prime_UTR	Exon 5 of 5	ENSP00000308937.3	Q01453
PMP22	ENST00000395938.7	TSL:1	c.*362C>T	3_prime_UTR	Exon 5 of 5	ENSP00000379269.3	A0A6Q8PF08
PMP22	ENST00000494511.7	TSL:1	c.*544C>T	3_prime_UTR	Exon 3 of 3	ENSP00000462782.2	J3KT36

Frequencies

GnomAD3 genomes

AF:

0.0000737

AC:

AN:

135746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000756

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000208

Gnomad SAS

AF:

0.000243

Gnomad FIN

AF:

0.000110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000676

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

6298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

3304

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

1272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

272

South Asian (SAS)

AF:

0.00

AC:

AN:

592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

3398

Other (OTH)

AF:

0.00

AC:

AN:

204

GnomAD4 genome

AF:

0.0000737

AC:

AN:

135746

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

66056

show subpopulations

African (AFR)

AF:

0.0000756

AC:

AN:

39678

American (AMR)

AF:

0.00

AC:

AN:

12954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3050

East Asian (EAS)

AF:

0.000208

AC:

AN:

4806

South Asian (SAS)

AF:

0.000243

AC:

AN:

4118

European-Finnish (FIN)

AF:

0.000110

AC:

AN:

9118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000676

AC:

AN:

59208

Other (OTH)

AF:

0.00

AC:

AN:

1864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease, type I (1)

Hereditary liability to pressure palsies (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.0

(source)

DANN

Benign

0.57

PhyloP100

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over