rs181810413
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001354604.2(MITF):c.880+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,578,934 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0031 ( 4 hom. )
Consequence
MITF
NM_001354604.2 intron
NM_001354604.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.860
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 (BayesDel_noAF=-0.84).
BP6
?
Variant 3-69949177-C-G is Benign according to our data. Variant chr3-69949177-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 226729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69949177-C-G is described in Lovd as [Benign]. Variant chr3-69949177-C-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00199 (303/152204) while in subpopulation NFE AF= 0.00338 (230/68016). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 303 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MITF | NM_000248.4 | c.559+9C>G | intron_variant | ENST00000394351.9 | |||
MITF | NM_001354604.2 | c.880+9C>G | intron_variant | ENST00000352241.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.880+9C>G | intron_variant | 1 | NM_001354604.2 | P4 | |||
MITF | ENST00000394351.9 | c.559+9C>G | intron_variant | 1 | NM_000248.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00199 AC: 303AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00184 AC: 461AN: 251028Hom.: 2 AF XY: 0.00175 AC XY: 238AN XY: 135686
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GnomAD4 exome AF: 0.00313 AC: 4467AN: 1426730Hom.: 4 Cov.: 25 AF XY: 0.00307 AC XY: 2188AN XY: 712216
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GnomAD4 genome ? AF: 0.00199 AC: 303AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00171 AC XY: 127AN XY: 74410
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | 880+9C>G in intron 6 of MITF: This variant is not expected to have clinical sign ificance because it is not located within the conserved splice consensus sequenc e. It has been identified in 0.3% (30/8600) of European American chromosomes fro m a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washin gton.edu/EVS; dbSNP rs181810413). - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 24, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 04, 2016 | Variant summary: c.559+9C>G affects a non-conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be a polymorphism. 4/5 in-silico tool predicts no significant changes on RNA splicing. ESEfinder predicts gain of binding motifs for RNA slicing enhancers. This variant was found in 196/120978 control chromosomes at a frequency of 0.0016201, which is more than 129 times of maximal expected frequency of a pathogenic allele (0.0000125), suggesting this variant is benign. . This variant has not been, to our knowledge, reported in affected individuals via publications/ clinical laboratories, or databases; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign. - |
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Tietz syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 22, 2020 | - - |
Waardenburg syndrome type 2A Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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