Genetic Variant MITF:c.104+68C>A (chr3-69739769-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001354604.2(MITF):c.104+68C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,049,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

MITF
NM_001354604.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.265

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354604.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MITF	NM_001354604.2	MANE Select	c.104+68C>A	intron	N/A	NP_001341533.1	O75030-1
MITF	NM_001354605.2		c.104+68C>A	intron	N/A	NP_001341534.1
MITF	NM_198159.3		c.104+68C>A	intron	N/A	NP_937802.1	O75030-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MITF	ENST00000352241.9	TSL:1 MANE Select	c.104+68C>A	intron	N/A	ENSP00000295600.8	O75030-1
MITF	ENST00000956046.1		c.104+68C>A	intron	N/A	ENSP00000626105.1
MITF	ENST00000956043.1		c.104+68C>A	intron	N/A	ENSP00000626102.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000190

AC:

AN:

1049914

Hom.:

AF XY:

0.00000376

AC XY:

AN XY:

531840

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24642

American (AMR)

AF:

0.00

AC:

AN:

34866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22932

East Asian (EAS)

AF:

0.00

AC:

AN:

34024

South Asian (SAS)

AF:

0.00

AC:

AN:

71838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4982

European-Non Finnish (NFE)

AF:

0.00000262

AC:

AN:

761926

Other (OTH)

AF:

0.00

AC:

AN:

46524

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.27

PromoterAI

-0.00050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over