3-69959313-G-C

Variant names:

• chr3-69959313-G-C
• rs1271000541
• NM_001354604.2:c.1072G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001354604.2(MITF):​c.1072G>C​(p.Val358Leu) 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. 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. V358M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 4 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: G2P, Orphanet, Ambry Genetics
• Waardenburg syndrome type 2

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

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

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

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001354604.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354604.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.1072G>C	p.Val358Leu	missense	Exon 9 of 10	NP_001341533.1
	MITF	NM_000248.4	MANE Plus Clinical	c.751G>C	p.Val251Leu	missense	Exon 8 of 9	NP_000239.1
	MITF	NM_001354605.2		c.1069G>C	p.Val357Leu	missense	Exon 9 of 10	NP_001341534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.1072G>C	p.Val358Leu	missense	Exon 9 of 10	ENSP00000295600.8
	MITF	ENST00000394351.9	TSL:1 MANE Plus Clinical	c.751G>C	p.Val251Leu	missense	Exon 8 of 9	ENSP00000377880.3
	MITF	ENST00000314557.10	TSL:1	c.733G>C	p.Val245Leu	missense	Exon 8 of 9	ENSP00000324246.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.65		Gain of catalytic residue at V352 (P = 0.0017)
MVP		0.98
MPC		0.93
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.92
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1271000541; hg19: chr3-70008464;