3-69879358-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001354604.2(MITF):​c.329C>T​(p.Thr110Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,212 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T110T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MITF
NM_001354604.2 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1092709).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000184 (28/152330) while in subpopulation AMR AF= 0.000327 (5/15306). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MITFNM_001354604.2 linkuse as main transcriptc.329C>T p.Thr110Met missense_variant 2/10 ENST00000352241.9 NP_001341533.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MITFENST00000352241.9 linkuse as main transcriptc.329C>T p.Thr110Met missense_variant 2/101 NM_001354604.2 ENSP00000295600.8 O75030-1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.000165
AC:
41
AN:
248876
Hom.:
0
AF XY:
0.000178
AC XY:
24
AN XY:
135056
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000231
Gnomad OTH exome
AF:
0.000495
GnomAD4 exome
AF:
0.000139
AC:
203
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.000158
AC XY:
115
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000197
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000138
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.000247
Hom.:
0
Bravo
AF:
0.000204
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000353
AC:
3
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.000491
EpiControl
AF:
0.000356

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 16, 2015The p.Thr110Met variant in MITF has not been previously reported in individuals with hearing loss, but has been identified in 15/66632 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 90215588). Although this variant has been seen in the general population, its fr equency is not high enough to rule out a pathogenic role. Computational predicti on tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr110Met variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
MITF-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 27, 2023The MITF c.329C>T variant is predicted to result in the amino acid substitution p.Thr110Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/228855). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
.;T;.;.;T;.;T;.;.;T
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
.;T;T;D;T;D;D;T;T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;L;L;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.90
N;N;.;N;N;N;D;N;N;N
REVEL
Benign
0.096
Sift
Benign
0.12
T;T;.;T;T;T;D;T;T;T
Sift4G
Benign
0.071
T;T;.;D;T;T;D;T;T;T
Polyphen
0.54
P;.;P;.;.;.;.;B;P;.
Vest4
0.47
MVP
0.25
MPC
0.32
ClinPred
0.091
T
GERP RS
6.0
Varity_R
0.055
gMVP
0.62

Splicing

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: rs190215588; hg19: chr3-69928509; COSMIC: COSV58882407; COSMIC: COSV58882407; API