3-69967753-C-T

Variant names:

• chr3-69967753-C-T
• rs704246
• NM_001354604.2:c.*2505C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001354604.2(MITF):​c.*2505C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 232,652 control chromosomes in the GnomAD database, including 9,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6570 hom., cov: 32)
  • Exomes 𝑓: 0.28 (3233 hom.)
• Consequence: MITF NM_001354604.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.359
• Publications: 8 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, Ambry Genetics, 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-69967753-C-T is Benign according to our data. Variant chr3-69967753-C-T is described in ClinVar as Benign. ClinVar VariationId is 346538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 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.*2505C>T		3_prime_UTR	Exon 10 of 10	NP_001341533.1	O75030-1
	MITF	NM_000248.4	MANE Plus Clinical	c.*2505C>T		3_prime_UTR	Exon 9 of 9	NP_000239.1	O75030-9
	MITF	NM_001354605.2		c.*2505C>T		3_prime_UTR	Exon 10 of 10	NP_001341534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.*2505C>T		3_prime_UTR	Exon 10 of 10	ENSP00000295600.8	O75030-1
	MITF	ENST00000394351.9	TSL:1 MANE Plus Clinical	c.*2505C>T		3_prime_UTR	Exon 9 of 9	ENSP00000377880.3	O75030-9
	MITF	ENST00000642352.1		c.*2505C>T		3_prime_UTR	Exon 10 of 10	ENSP00000494105.1	O75030-2

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44299 AN: 151860 Hom.: 6552 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.279 AC: 22485 AN: 80674 Hom.: 3233 Cov.: 0 AF XY: 0.278 AC XY: 10326 AN XY: 37088

African (AFR) AF: 0.356 AC: 1379 AN: 3874

American (AMR) AF: 0.303 AC: 752 AN: 2482

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 1395 AN: 5114

East Asian (EAS) AF: 0.309 AC: 3522 AN: 11380

South Asian (SAS) AF: 0.310 AC: 217 AN: 700

European-Finnish (FIN) AF: 0.297 AC: 19 AN: 64

Middle Eastern (MID) AF: 0.239 AC: 117 AN: 490

European-Non Finnish (NFE) AF: 0.267 AC: 13316 AN: 49814

Other (OTH) AF: 0.262 AC: 1768 AN: 6756

GnomAD4 genome AF: 0.292 AC: 44346 AN: 151978 Hom.: 6570 Cov.: 32 AF XY: 0.291 AC XY: 21622 AN XY: 74258

African (AFR) AF: 0.348 AC: 14418 AN: 41456

American (AMR) AF: 0.288 AC: 4394 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 928 AN: 3466

East Asian (EAS) AF: 0.269 AC: 1391 AN: 5164

South Asian (SAS) AF: 0.296 AC: 1427 AN: 4814

European-Finnish (FIN) AF: 0.272 AC: 2873 AN: 10564

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18140 AN: 67960

Other (OTH) AF: 0.267 AC: 563 AN: 2110

Alfa AF: 0.275 Hom.: 15392

Bravo AF: 0.296

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Tietz syndrome (1)
-	-	1	Waardenburg syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.71
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs704246; hg19: chr3-70016904;