rs373660547
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001354604.2(MITF):c.104+24226G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 1,367,218 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
MITF
NM_001354604.2 intron
NM_001354604.2 intron
Scores
3
13
Clinical Significance
Conservation
PhyloP100: 0.858
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 -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.011420697).
BP6
?
Variant 3-69763927-G-A is Benign according to our data. Variant chr3-69763927-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228854.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000499 (76/152336) while in subpopulation AFR AF= 0.00178 (74/41584). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 76 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MITF | NM_001354604.2 | c.104+24226G>A | intron_variant | ENST00000352241.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.104+24226G>A | intron_variant | 1 | NM_001354604.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000499 AC: 76AN: 152218Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000106 AC: 20AN: 189342Hom.: 0 AF XY: 0.0000697 AC XY: 7AN XY: 100444
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GnomAD4 exome AF: 0.0000370 AC: 45AN: 1214882Hom.: 0 Cov.: 31 AF XY: 0.0000251 AC XY: 15AN XY: 596560
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GnomAD4 genome ? AF: 0.000499 AC: 76AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34AN XY: 74488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 15, 2021 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 05, 2021 | The p.Cys29Tyr/c.86G>A variant in MITF (NM_006722.2) is classified as benign because it has been identified in 0.17% (34/20,000) of African/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP4. - |
MITF-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 03, 2022 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.0
.;B
Vest4
0.15
MVP
ClinPred
T
GERP RS
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at