chr3-69866345-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001354604.2(MITF):​c.105-12789C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,366 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MITF
NM_001354604.2 intron

Scores

3
13
Splicing: ADA: 0.7931
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13689339).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MITFNM_001354604.2 linkuse as main transcriptc.105-12789C>T intron_variant ENST00000352241.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MITFENST00000352241.9 linkuse as main transcriptc.105-12789C>T intron_variant 1 NM_001354604.2 P4O75030-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461366
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726946
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 18, 2016The p.Leu19Phe variant in MITF has not been previously reported in individuals w ith hearing loss or Waardenburg syndrome and was absent from large population st udies. Computational prediction tools and conservation analysis suggest that thi s variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p .Leu19Phe variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
.;T
Eigen
Benign
-0.086
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D;D;D;N
PROVEAN
Benign
-0.49
N;N
REVEL
Benign
0.042
Sift
Uncertain
0.017
D;D
Sift4G
Benign
0.17
T;T
Polyphen
0.0010
B;.
Vest4
0.34
MutPred
0.11
Gain of glycosylation at Y18 (P = 0.0054);Gain of glycosylation at Y18 (P = 0.0054);
MVP
0.26
ClinPred
0.60
D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.79
dbscSNV1_RF
Benign
0.58

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761597919; hg19: chr3-69915496; COSMIC: COSV58886108; API