chr12-55956963-G-A
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2
The NM_001384361.1(PMEL):c.1340C>T(p.Thr447Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,064 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.0072 ( 20 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 9 hom. )
Consequence
PMEL
NM_001384361.1 missense
NM_001384361.1 missense
Scores
6
11
Clinical Significance
Conservation
PhyloP100: 1.29
Genes affected
PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0036189854).
BP6
?
Variant 12-55956963-G-A is Benign according to our data. Variant chr12-55956963-G-A is described in ClinVar as [Benign]. Clinvar id is 713129.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00716 (1090/152286) while in subpopulation AFR AF= 0.0252 (1048/41558). AF 95% confidence interval is 0.0239. There are 20 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 16 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMEL | NM_001384361.1 | c.1340C>T | p.Thr447Met | missense_variant | 6/11 | ENST00000548747.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMEL | ENST00000548747.6 | c.1340C>T | p.Thr447Met | missense_variant | 6/11 | 1 | NM_001384361.1 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00705 AC: 1073AN: 152168Hom.: 16 Cov.: 32
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GnomAD3 exomes AF: 0.00172 AC: 428AN: 248840Hom.: 5 AF XY: 0.00124 AC XY: 167AN XY: 134680
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GnomAD4 exome AF: 0.000649 AC: 948AN: 1461778Hom.: 9 Cov.: 32 AF XY: 0.000576 AC XY: 419AN XY: 727188
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GnomAD4 genome ? AF: 0.00716 AC: 1090AN: 152286Hom.: 20 Cov.: 32 AF XY: 0.00720 AC XY: 536AN XY: 74476
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Mar 29, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;.;T;T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;L;L;.
MutationTaster
Benign
D;D;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;D;D;D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -14
Find out detailed SpliceAI scores and Pangolin per-transcript scores at