rs36118030

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001354604.2(MITF):c.1566G>A(p.Thr522Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,830 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 27 hom. )

Consequence

MITF
NM_001354604.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.82

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]

MITF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 3-69965233-G-A is Benign according to our data. Variant chr3-69965233-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69965233-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.82 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00888 (1352/152280) while in subpopulation AFR AF= 0.0307 (1278/41564). AF 95% confidence interval is 0.0293. There are 13 homozygotes in gnomad4. There are 671 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1352 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2 link	c.1566G>A	p.Thr522Thr	synonymous_variant	Exon 10 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4 link	c.1245G>A	p.Thr415Thr	synonymous_variant	Exon 9 of 9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9 link	c.1566G>A	p.Thr522Thr	synonymous_variant	Exon 10 of 10	1	NM_001354604.2	ENSP00000295600.8		O75030-1
MITF	ENST00000394351.9 link	c.1245G>A	p.Thr415Thr	synonymous_variant	Exon 9 of 9	1	NM_000248.4	ENSP00000377880.3		O75030-9

Frequencies

GnomAD3 genomes

AF:

0.00889

AC:

1353

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00216

AC:

541

AN:

249940

Hom.:

AF XY:

0.00156

AC XY:

211

AN XY:

135150

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000898

AC:

1313

AN:

1461550

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

531

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0317

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00888

AC:

1352

AN:

152280

Hom.:

Cov.:

AF XY:

0.00901

AC XY:

671

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0307

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00432

Hom.:

Bravo

AF:

0.0110

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 12, 2022

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr516Thr in exon 10 of MITF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.7% (120/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs36118030). -

not provided

Benign:3

Mar 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MITF c.1245G>A affects a non-conserved nucleotide, resulting in a synonymous change. 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 323/120562 control chromosomes at a frequency of 0.0026791, predominalty observed in African subpopulation in ExAC with MAF of 0.031 with 8 homozygotes. These frequencies significantly exceed the maximal expected frequency of a pathogenic MITF allele (0.0000125), suggesting this variant is benign. This variant has not, to our knowledge, been reported in affected individuals via publications or clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign. -

Dec 05, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Waardenburg syndrome type 2A

Benign:2

Jan 13, 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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tietz syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

- -

Hereditary cancer-predisposing syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.44

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over