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, 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2	c.*2505C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.*2505C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.*2505C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.*2505C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000248.4	ENSP00000377880.3

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tietz syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Waardenburg syndrome type 2A Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;