rs1036051

Variant names:

• chr3-69850216-C-T
• rs1036051
• NM_001354604.2:c.105-28918C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354604.2(MITF):​c.105-28918C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 151,954 control chromosomes in the GnomAD database, including 20,097 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (20097 hom., cov: 32)
• Consequence: MITF NM_001354604.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 2 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: Orphanet, ClinGen
• Waardenburg syndrome type 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.105-28918C>T		intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_001354605.2		c.105-28921C>T		intron	N/A	NP_001341534.1
	MITF	NM_198159.3		c.105-28918C>T		intron	N/A	NP_937802.1	O75030-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.105-28918C>T		intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000956046.1		c.105-28918C>T		intron	N/A	ENSP00000626105.1
	MITF	ENST00000956043.1		c.105-28918C>T		intron	N/A	ENSP00000626102.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74675 AN: 151836 Hom.: 20084 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.529

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.492 AC: 74721 AN: 151954 Hom.: 20097 Cov.: 32 AF XY: 0.485 AC XY: 35989 AN XY: 74272

African (AFR) AF: 0.314 AC: 12999 AN: 41420

American (AMR) AF: 0.415 AC: 6346 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1893 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5154

South Asian (SAS) AF: 0.338 AC: 1626 AN: 4816

European-Finnish (FIN) AF: 0.593 AC: 6245 AN: 10538

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42673 AN: 67972

Other (OTH) AF: 0.524 AC: 1104 AN: 2108

Alfa AF: 0.525 Hom.: 3873

Bravo AF: 0.470

Asia WGS AF: 0.268 AC: 936 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.22
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs1036051;

hg19: chr3-69899367;