NM_000304.4:c.319+33C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

1
7

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.519

Publications

8 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: 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank MANE Protein UniProt
PMP22NM_000304.4 linkc.319+33C>T intron_variant Intron 4 of 4 ENST00000312280.9 NP_000295.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMP22ENST00000312280.9 linkc.319+33C>T intron_variant Intron 4 of 4 1 NM_000304.4 ENSP00000308937.3 Q01453

Frequencies

GnomAD3 genomes
AF:
0.0652
AC:
9912
AN:
152118
Hom.:
484
Cov.:
33
show subpopulations
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
GnomAD2 exomes
AF:
0.0847
AC:
21288
AN:
251458
AF XY:
0.0898
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.0182
AC:
608
AN:
33462
American (AMR)
AF:
0.0438
AC:
1961
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.109
AC:
2844
AN:
26120
East Asian (EAS)
AF:
0.156
AC:
6184
AN:
39684
South Asian (SAS)
AF:
0.140
AC:
12112
AN:
86214
European-Finnish (FIN)
AF:
0.0420
AC:
2243
AN:
53418
Middle Eastern (MID)
AF:
0.0922
AC:
532
AN:
5768
European-Non Finnish (NFE)
AF:
0.0828
AC:
91911
AN:
1110372
Other (OTH)
AF:
0.0851
AC:
5131
AN:
60306
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
5789
11578
17368
23157
28946
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
3474
6948
10422
13896
17370
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0651
AC:
9910
AN:
152236
Hom.:
484
Cov.:
33
AF XY:
0.0633
AC XY:
4709
AN XY:
74430
show subpopulations
African (AFR)
AF:
0.0195
AC:
808
AN:
41540
American (AMR)
AF:
0.0553
AC:
846
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.123
AC:
427
AN:
3470
East Asian (EAS)
AF:
0.173
AC:
893
AN:
5170
South Asian (SAS)
AF:
0.149
AC:
716
AN:
4816
European-Finnish (FIN)
AF:
0.0372
AC:
394
AN:
10598
Middle Eastern (MID)
AF:
0.0918
AC:
27
AN:
294
European-Non Finnish (NFE)
AF:
0.0824
AC:
5603
AN:
68024
Other (OTH)
AF:
0.0734
AC:
155
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
477
953
1430
1906
2383
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
124
248
372
496
620
<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:
0.0620
Hom.:
189
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
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 26, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Charcot-Marie-Tooth disease, type I Benign:1
Jan 30, 2019
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
PhyloP100
-0.52
Sift4G
Uncertain
0.043
D
Vest4
0.079
GERP RS
-2.2
Mutation Taster
=99/1
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

Publications

Other links and lift over

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