Variant chr3-69879137-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001354604.2(MITF):c.108T>G(p.Ser36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MITF
NM_001354604.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23487431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_001354604.2 linkuse as main transcript	c.108T>G	p.Ser36Arg	missense_variant	2/10	ENST00000352241.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9 linkuse as main transcript	c.108T>G	p.Ser36Arg	missense_variant	2/10	1	NM_001354604.2	P4	O75030-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MITF-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2023

The MITF c.108T>G variant is predicted to result in the amino acid substitution p.Ser36Arg. This variant corresponds to a precoding variant in the primary transcript for this gene (NM_000248.3:c.-57586T>G). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

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

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.022

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.1

M;M;M;.;.;.;.

MutationTaster

Benign

0.94

D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.4

N;N;.;D;N;N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0030

D;D;.;T;D;D;D

Sift4G

Benign

0.26

T;T;.;D;D;T;T

Polyphen

0.34

B;.;B;.;P;B;.

Vest4

0.35

MutPred

0.30

Loss of phosphorylation at S36 (P = 0.0054);Loss of phosphorylation at S36 (P = 0.0054);Loss of phosphorylation at S36 (P = 0.0054);.;.;.;.;

MVP

0.36

MPC

0.75

ClinPred

0.90

GERP RS

5.9

Varity_R

0.45

gMVP

0.76

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