rs1553704086

chr3-69951856-G-Achr3-69951856-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001354604.2(MITF):c.925G>A(p.Glu309Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E309E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001354604.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• PP5: Variant 3-69951856-G-A is Pathogenic according to our data. Variant chr3-69951856-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545452.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_001354604.2	c.925G>A	p.Glu309Lys	missense_variant	7/10	ENST00000352241.9
MITF	NM_000248.4	c.604G>A	p.Glu202Lys	missense_variant	6/9	ENST00000394351.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.925G>A	p.Glu309Lys	missense_variant	7/10	1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.604G>A	p.Glu202Lys	missense_variant	6/9	1	NM_000248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tietz syndrome;C1860339:Waardenburg syndrome type 2A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jun 01, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D;D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;.;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.;D;D;.
Vest4		0.61
MutPred		0.31		Gain of MoRF binding (P = 0.0055);.;Gain of MoRF binding (P = 0.0055);.;.;.;.;.;.;.;
MVP		0.91
MPC		0.38
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1553704086; hg19: chr3-70001007;