rs140663277

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001354604.2(MITF):​c.366C>T​(p.His122His) variant causes a synonymous change. The variant allele was found at a frequency of 0.00314 in 1,613,980 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 18 hom. )

Consequence

MITF
NM_001354604.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 6.06
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 -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 3-69937833-C-T is Benign according to our data. Variant chr3-69937833-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69937833-C-T is described in Lovd as [Benign]. Variant chr3-69937833-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00207 (315/152262) while in subpopulation SAS AF= 0.00477 (23/4820). AF 95% confidence interval is 0.00326. There are 0 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 315 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MITFNM_001354604.2 linkc.366C>T p.His122His synonymous_variant Exon 3 of 10 ENST00000352241.9 NP_001341533.1
MITFNM_000248.4 linkc.45C>T p.His15His synonymous_variant Exon 2 of 9 ENST00000394351.9 NP_000239.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MITFENST00000352241.9 linkc.366C>T p.His122His synonymous_variant Exon 3 of 10 1 NM_001354604.2 ENSP00000295600.8 O75030-1
MITFENST00000394351.9 linkc.45C>T p.His15His synonymous_variant Exon 2 of 9 1 NM_000248.4 ENSP00000377880.3 O75030-9

Frequencies

GnomAD3 genomes
AF:
0.00207
AC:
315
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00893
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00477
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00318
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.00289
AC:
725
AN:
250976
Hom.:
2
AF XY:
0.00318
AC XY:
431
AN XY:
135666
show subpopulations
Gnomad AFR exome
AF:
0.000862
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.0103
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00592
Gnomad FIN exome
AF:
0.000555
Gnomad NFE exome
AF:
0.00326
Gnomad OTH exome
AF:
0.00326
GnomAD4 exome
AF:
0.00325
AC:
4748
AN:
1461718
Hom.:
18
Cov.:
31
AF XY:
0.00328
AC XY:
2385
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.000872
Gnomad4 ASJ exome
AF:
0.0118
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00595
Gnomad4 FIN exome
AF:
0.000543
Gnomad4 NFE exome
AF:
0.00324
Gnomad4 OTH exome
AF:
0.00353
GnomAD4 genome
AF:
0.00207
AC:
315
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.00188
AC XY:
140
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.000578
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00893
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00477
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00318
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.00339
Hom.:
1
Bravo
AF:
0.00205
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.00360
EpiControl
AF:
0.00332

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:6
Feb 21, 2019
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MITF: BP4, BS2 -

Feb 12, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

not specified Benign:3
Nov 24, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

His122His in exon 3 of MITF: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.3% (30/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs140663277). -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Oct 02, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Oct 09, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Waardenburg syndrome type 2A Benign:2
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tietz syndrome Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

MITF-related disorder Benign:1
Jul 20, 2020
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as 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
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
13
DANN
Benign
0.62
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs140663277; hg19: chr3-69986984; API