3-69763927-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006722.3(MITF):c.86G>A(p.Cys29Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 1,367,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

MITF
NM_006722.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.858

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Tietz syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
Waardenburg syndrome type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Waardenburg syndrome type 2A
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
melanoma, cutaneous malignant, susceptibility to, 8
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Waardenburg syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Waardenburg-Shah syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MITF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011420697).

BP6

Variant 3-69763927-G-A is Benign according to our data. Variant chr3-69763927-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228854.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000499 (76/152336) while in subpopulation AFR AF = 0.00178 (74/41584). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006722.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MITF	NM_001354604.2	MANE Select	c.104+24226G>A		intron	N/A	NP_001341533.1	O75030-1
MITF	NM_006722.3		c.86G>A	p.Cys29Tyr	missense	Exon 1 of 10	NP_006713.1	O75030-6
MITF	NM_001354605.2		c.104+24226G>A		intron	N/A	NP_001341534.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MITF	ENST00000352241.9	TSL:1 MANE Select	c.104+24226G>A		intron	N/A	ENSP00000295600.8	O75030-1
MITF	ENST00000448226.9	TSL:5	c.86G>A	p.Cys29Tyr	missense	Exon 1 of 10	ENSP00000391803.3	O75030-6
MITF	ENST00000956046.1		c.104+24226G>A		intron	N/A	ENSP00000626105.1

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000106

AC:

AN:

189342

AF XY:

0.0000697

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.0000713

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000370

AC:

AN:

1214882

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

596560

show subpopulations

African (AFR)

AF:

0.00151

AC:

AN:

27132

American (AMR)

AF:

0.0000915

AC:

AN:

32784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18682

East Asian (EAS)

AF:

0.00

AC:

AN:

22470

South Asian (SAS)

AF:

0.00

AC:

AN:

78210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

955072

Other (OTH)

AF:

0.0000219

AC:

AN:

45740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000499

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000672

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

MITF-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.44

M_CAP

Benign

0.0030

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

PhyloP100

0.86

PROVEAN

Benign

0.44

REVEL

Benign

0.014

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0030

Polyphen

0.0

Vest4

0.15

MVP

0.068

ClinPred

0.014

GERP RS

3.3

PromoterAI

-0.15

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over