rs36118030
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001354604.2(MITF):c.1566G>A(p.Thr522=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,830 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0089 ( 13 hom., cov: 32)
Exomes 𝑓: 0.00090 ( 27 hom. )
Consequence
MITF
NM_001354604.2 synonymous
NM_001354604.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.82
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 3-69965233-G-A is Benign according to our data. Variant chr3-69965233-G-A is described in ClinVar as [Benign]. Clinvar id is 226726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69965233-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-3.82 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00888 (1352/152280) while in subpopulation AFR AF= 0.0307 (1278/41564). AF 95% confidence interval is 0.0293. There are 13 homozygotes in gnomad4. There are 671 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1352 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MITF | NM_001354604.2 | c.1566G>A | p.Thr522= | synonymous_variant | 10/10 | ENST00000352241.9 | NP_001341533.1 | |
| MITF | NM_000248.4 | c.1245G>A | p.Thr415= | synonymous_variant | 9/9 | ENST00000394351.9 | NP_000239.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MITF | ENST00000352241.9 | c.1566G>A | p.Thr522= | synonymous_variant | 10/10 | 1 | NM_001354604.2 | ENSP00000295600 | P4 | |
| MITF | ENST00000394351.9 | c.1245G>A | p.Thr415= | synonymous_variant | 9/9 | 1 | NM_000248.4 | ENSP00000377880 |
Frequencies
GnomAD3 genomes 0.00889 AC: 1353AN: 152162Hom.: 13 Cov.: 32
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GnomAD3 exomes AF: 0.00216 AC: 541AN: 249940Hom.: 12 AF XY: 0.00156 AC XY: 211AN XY: 135150
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GnomAD4 exome AF: 0.000898 AC: 1313AN: 1461550Hom.: 27 Cov.: 31 AF XY: 0.000730 AC XY: 531AN XY: 727008
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GnomAD4 genome 0.00888 AC: 1352AN: 152280Hom.: 13 Cov.: 32 AF XY: 0.00901 AC XY: 671AN XY: 74458
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | Thr516Thr in exon 10 of MITF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.7% (120/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs36118030). - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2018 | 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, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | May 12, 2022 | - - |
not provided Benign:3
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 04, 2016 | Variant summary: MITF c.1245G>A affects a non-conserved nucleotide, resulting in a synonymous change. 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 323/120562 control chromosomes at a frequency of 0.0026791, predominalty observed in African subpopulation in ExAC with MAF of 0.031 with 8 homozygotes. These frequencies significantly exceed the maximal expected frequency of a pathogenic MITF allele (0.0000125), suggesting this variant is benign. This variant has not, to our knowledge, been reported in affected individuals via publications or clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign. - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 05, 2018 | - - |
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2022 | - - |
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 | - - |
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
Source:
Name
Calibrated prediction
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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