rs140663277

Variant names:

• chr3-69937833-C-T
• rs140663277
• NM_001354604.2:c.366C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 6.06

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]

ACMG classification

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
MITF	NM_001354604.2	c.366C>T	p.His122His	synonymous_variant	Exon 3 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.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
MITF	ENST00000352241.9	c.366C>T	p.His122His	synonymous_variant	Exon 3 of 10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.45C>T	p.His15His	synonymous_variant	Exon 2 of 9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152144 Hom.: 0 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2024	MITF: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2019	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 27, 2021	- -

Waardenburg syndrome type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Feb 01, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 02, 2024	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. -

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

Feb 04, 2025

- -

MITF-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 20, 2020

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). -

Tietz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

- -

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

Other links and lift over

dbSNP: rs140663277; hg19: chr3-69986984;