3-69763927-G-C

Variant names:

• chr3-69763927-G-C
• rs373660547
• NM_001354604.2:c.104+24226G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006722.3(MITF):​c.86G>C​(p.Cys29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000823 in 1,214,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: MITF NM_006722.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.858

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08270529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2	c.104+24226G>C		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	c.104+24226G>C		intron_variant	Intron 1 of 9	1	NM_001354604.2	ENSP00000295600.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000528 AC: 1 AN: 189342 Hom.: 0 AF XY: 0.00000996 AC XY: 1 AN XY: 100444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.23e-7 AC: 1 AN: 1214884 Hom.: 0 Cov.: 31 AF XY: 0.00000168 AC XY: 1 AN XY: 596560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000840 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.013
Sift	Uncertain	0.010	D;T
Sift4G	Uncertain	0.036	D;D
Polyphen		0.0040	.;B
Vest4		0.24
MutPred		0.41		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.11
ClinPred		0.066	T
GERP RS		3.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373660547; hg19: chr3-69813078;