rs200108255

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001354604.2(MITF):ā€‹c.623A>Gā€‹(p.Glu208Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,120 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 Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 32)
Exomes š‘“: 0.000045 ( 0 hom. )

Consequence

MITF
NM_001354604.2 missense

Scores

9
10

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.71
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0074884593).
BP6
Variant 3-69939138-A-G is Benign according to our data. Variant chr3-69939138-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000125 (19/152324) while in subpopulation EAS AF= 0.00367 (19/5180). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MITFNM_001354604.2 linkuse as main transcriptc.623A>G p.Glu208Gly missense_variant 4/10 ENST00000352241.9 NP_001341533.1
MITFNM_000248.4 linkuse as main transcriptc.302A>G p.Glu101Gly missense_variant 3/9 ENST00000394351.9 NP_000239.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MITFENST00000352241.9 linkuse as main transcriptc.623A>G p.Glu208Gly missense_variant 4/101 NM_001354604.2 ENSP00000295600 P4O75030-1
MITFENST00000394351.9 linkuse as main transcriptc.302A>G p.Glu101Gly missense_variant 3/91 NM_000248.4 ENSP00000377880 O75030-9

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00366
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000219
AC:
55
AN:
251172
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00300
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000451
AC:
66
AN:
1461796
Hom.:
0
Cov.:
32
AF XY:
0.0000371
AC XY:
27
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00149
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152324
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00367
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.000157
AC:
19
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 17, 2015p.Glu208Gly in exon 4 of MITF: This variant is not expected to have clinical sig nficance because it has been in 0.22% (19/8540) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200 108255). -
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
MITF-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 14, 2024This 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). -
Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 12, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
.;T;.;T;.;.;.;T;.;.;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
.;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.0075
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L;L;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.48
N;N;.;N;N;N;N;N;N;N;N
REVEL
Benign
0.16
Sift
Uncertain
0.0080
D;D;.;T;D;D;D;D;D;D;T
Sift4G
Benign
0.59
T;T;.;T;T;T;T;T;T;T;T
Polyphen
0.86
P;.;P;.;.;P;D;.;P;P;.
Vest4
0.74
MVP
0.72
MPC
0.59
ClinPred
0.094
T
GERP RS
6.0
Varity_R
0.076
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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: rs200108255; hg19: chr3-69988289; API