3-69763927-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006722.3(MITF):​c.86G>T​(p.Cys29Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C29Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MITF NM_006722.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.858
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Tietz syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Waardenburg syndrome type 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• melanoma, cutaneous malignant, susceptibility to, 8

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Waardenburg syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Waardenburg-Shah syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08407053).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006722.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.104+24226G>T		intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_006722.3		c.86G>T	p.Cys29Phe	missense	Exon 1 of 10	NP_006713.1	O75030-6
	MITF	NM_001354605.2		c.104+24226G>T		intron	N/A	NP_001341534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.104+24226G>T		intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000448226.9	TSL:5	c.86G>T	p.Cys29Phe	missense	Exon 1 of 10	ENSP00000391803.3	O75030-6
	MITF	ENST00000956046.1		c.104+24226G>T		intron	N/A	ENSP00000626105.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1214884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 596560

African (AFR) AF: 0.00 AC: 0 AN: 27132

American (AMR) AF: 0.00 AC: 0 AN: 32784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18682

East Asian (EAS) AF: 0.00 AC: 0 AN: 22470

South Asian (SAS) AF: 0.00 AC: 0 AN: 78210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 955072

Other (OTH) AF: 0.00 AC: 0 AN: 45742

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.86
PROVEAN	Benign	0.060	N
REVEL	Benign	0.018
Sift	Benign	0.11	T
Sift4G	Uncertain	0.0040	D
PromoterAI		0.087	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373660547;

hg19: chr3-69813078;