rs200108255
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001354604.2(MITF):āc.623A>Gā(p.Glu208Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,120 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 Likely benign (ā ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.000045 ( 0 hom. )
Consequence
MITF
NM_001354604.2 missense
NM_001354604.2 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 5.71
Genes affected
MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0074884593).
BP6
Variant 3-69939138-A-G is Benign according to our data. Variant chr3-69939138-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000125 (19/152324) while in subpopulation EAS AF= 0.00367 (19/5180). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MITF | NM_001354604.2 | c.623A>G | p.Glu208Gly | missense_variant | 4/10 | ENST00000352241.9 | NP_001341533.1 | |
MITF | NM_000248.4 | c.302A>G | p.Glu101Gly | missense_variant | 3/9 | ENST00000394351.9 | NP_000239.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.623A>G | p.Glu208Gly | missense_variant | 4/10 | 1 | NM_001354604.2 | ENSP00000295600 | P4 | |
MITF | ENST00000394351.9 | c.302A>G | p.Glu101Gly | missense_variant | 3/9 | 1 | NM_000248.4 | ENSP00000377880 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000219 AC: 55AN: 251172Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135742
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GnomAD4 exome AF: 0.0000451 AC: 66AN: 1461796Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727196
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74474
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 17, 2015 | p.Glu208Gly in exon 4 of MITF: This variant is not expected to have clinical sig nficance because it has been in 0.22% (19/8540) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200 108255). - |
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
MITF-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;T;.;.;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;N;N;N;N;N;N
REVEL
Benign
Sift
Uncertain
D;D;.;T;D;D;D;D;D;D;T
Sift4G
Benign
T;T;.;T;T;T;T;T;T;T;T
Polyphen
P;.;P;.;.;P;D;.;P;P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at