rs104893747

Positions:

chr3-69964880-T-C

Variant summary

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

The NM_001354604.2(MITF):c.1213T>C(p.Ser405Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

MITF
NM_001354604.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 1.75

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15746975).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0002 (293/1461868) while in subpopulation NFE AF= 0.000262 (291/1111992). AF 95% confidence interval is 0.000237. There are 1 homozygotes in gnomad4_exome. There are 140 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2 linkuse as main transcript	c.1213T>C	p.Ser405Pro	missense_variant	10/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4 linkuse as main transcript	c.892T>C	p.Ser298Pro	missense_variant	9/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9 linkuse as main transcript	c.1213T>C	p.Ser405Pro	missense_variant	10/10	1	NM_001354604.2	ENSP00000295600	P4	O75030-1
MITF	ENST00000394351.9 linkuse as main transcript	c.892T>C	p.Ser298Pro	missense_variant	9/9	1	NM_000248.4	ENSP00000377880		O75030-9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251382

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000200

AC:

293

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000262

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000894

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Waardenburg syndrome type 2A

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 25, 2022

Variant summary: MITF c.892T>C (p.Ser298Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251382 control chromosomes (gnomAD). c.892T>C has been reported in the literature as a heterozygous genotype in at least one affected individual from a family with a multi-generational history of Waardenburg Syndrome 2 (e.g. Tassabehji_1995) and has also been reported as a VUS in individuals with melanoma and head and neck squamous cell carcinoma (e.g. Huang_2018). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function, however with conflicting results. While the variant has been reported to impair DNA-binding and transactivational activity in one study (Takeda_2000), a different study found the variant protein had no effect on DNA-binding and resulted in mildly increased transcriptional activity at some promoters (Grill_2013). One clinical diagnostic laboratory has submitted a clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 298 of the MITF protein (p.Ser298Pro). This variant is present in population databases (rs104893747, gnomAD 0.007%). This missense change has been observed in individual(s) with cutaneous melanoma and/or Waardenburg syndrome, type 2 (PMID: 8589691, 29115496, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 14277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MITF protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MITF function (PMID: 10587587, 23787126). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

MITF-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The MITF c.892T>C variant is predicted to result in the amino acid substitution p.Ser298Pro. This variant has been reported to segregate with Type 2 Waardenburg syndrome in a multigenerational pedigree (Tassabehji et al. 1995. PubMed ID: 8589691). It has also been reported in an individual with head and neck squamous cell carcinoma and an individual with cutaneous melanoma (Huang et al. 2018. PubMed ID: 29625052, Table S2B, Chr3:g.70014031T>C). In vitro experimental studies provide conflicting results of this variants impact on protein function (Takeda et al. 2000. PubMed ID: 10587587; Grill et al. 2013. PubMed ID: 23787126). It is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14277/). 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 submitter

clinical testing

GeneDx

Jun 05, 2024

Published functional studies demonstrate conflicting results with respect to effect on DNA binding and phosphorylation abilities (PMID: 10587587, 23787126); Observed in individuals with melanoma or other cancers (PMID: 29625052); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28690485, 10587587, 10952390, 11764295, 23787126, 23098757, 29115496, 31589614, 36451132, 29625052, 8589691) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.36

DEOGEN2

Uncertain

0.54

.;D;.;.;.;.;.;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

.;T;T;T;T;T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.43

.;N;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.65

PROVEAN

Benign

2.0

N;N;.;N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;.;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;.;T;T;T;T;T;T

Polyphen

0.0030

B;.;B;.;B;B;B;B;.

Vest4

0.46

MVP

0.89

MPC

0.35

ClinPred

0.084

GERP RS

4.7

Varity_R

0.17

gMVP

0.32

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