rs869025259

Positions:

• chr3-69941305-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001354604.2(MITF):​c.736G>A​(p.Asp246Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

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=0.37838098).
• BP6: Variant 3-69941305-G-A is Benign according to our data. Variant chr3-69941305-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221940.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr3-69941305-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.736G>A	p.Asp246Asn	missense_variant	5/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.415G>A	p.Asp139Asn	missense_variant	4/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.736G>A	p.Asp246Asn	missense_variant	5/10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.415G>A	p.Asp139Asn	missense_variant	4/9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with sporadic ocular developmental anomalies (ODA) (Chassaing et al., 2016); This variant is associated with the following publications: (PMID: 26893459, Naveed2017[article]) -

Anophthalmia-microphthalmia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;.;T;.;.;.;T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T;D;D;D;D;D;D;D;T;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;L;L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N;N;.;D;N;N;N;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.30	T;T;.;T;T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;.;T;T;T;T;T;T;T;T
Polyphen		0.68	P;.;P;.;.;B;P;.;P;B;.
Vest4		0.80
MutPred		0.41		Gain of disorder (P = 0.315);Gain of disorder (P = 0.315);Gain of disorder (P = 0.315);.;.;.;.;.;.;.;.;
MVP		0.36
MPC		0.67
ClinPred		0.65	D
GERP RS		5.9
Varity_R		0.22
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs869025259; hg19: chr3-69990456; COSMIC: COSV58835494; COSMIC: COSV58835494;