3-69959370-C-G

Position:

• chr3-69959370-C-G

Variant summary

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

The NM_001354604.2(MITF):​c.1129C>G​(p.Arg377Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.1129C>G	p.Arg377Gly	missense_variant	9/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.808C>G	p.Arg270Gly	missense_variant	8/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.1129C>G	p.Arg377Gly	missense_variant	9/10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.808C>G	p.Arg270Gly	missense_variant	8/9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;D;.;D;D;D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;.;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.;D;D;.
Vest4		0.94
MutPred		0.33		Gain of ubiquitination at K374 (P = 0.0278);.;Gain of ubiquitination at K374 (P = 0.0278);.;.;.;.;.;.;.;
MVP		0.79
MPC		1.0
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.85
gMVP		0.82

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: rs876657699; hg19: chr3-70008521;