dbSNP rs779387274: MITF:c.105-12836C>T (chr3-69866298-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_198177.3(MITF):c.8C>T(p.Ala3Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MITF
NM_198177.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.67

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15411964).

BP6

Variant 3-69866298-C-T is Benign according to our data. Variant chr3-69866298-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227547.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2 link	c.105-12836C>T		intron_variant	Intron 1 of 9	ENST00000352241.9	NP_001341533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9 link	c.105-12836C>T		intron_variant	Intron 1 of 9	1	NM_001354604.2	ENSP00000295600.8		O75030-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

248930

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461442

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala3Val in exon 01c of MITF: This variant is not expected to have clinical si gnificance because the alanine (Ala) residue at position 3 is not conserved thro ugh species, with Egyptian jerboa, elephant and Cape elephant shrew all having a valine (Val) at this position. Additional computational analyses suggest that this variant may not impact the protein. It has been identified in 1/66732 Eur opean chromosomes and 1/16512 South Asian chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.24

.;T

Eigen

Benign

0.015

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.067

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.20

B;.

Vest4

0.41

MutPred

0.36

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.30

ClinPred

0.15

GERP RS

5.8

Splicing

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