3-69967753-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:2
• Conservation: PhyloP100: -0.359

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 346538.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
MITF	NM_000248.4	c.*2505C>T		3_prime_UTR_variant	9/9	ENST00000394351.9
MITF	NM_001354604.2	c.*2505C>T		3_prime_UTR_variant	10/10	ENST00000352241.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.*2505C>T		3_prime_UTR_variant	10/10	1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.*2505C>T		3_prime_UTR_variant	9/9	1	NM_000248.4

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

Gnomad4 AFR exome AF: 0.356

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.309

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.262

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

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.267

Alfa AF: 0.264 Hom.: 8708

Bravo AF: 0.296

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Tietz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Waardenburg syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs704246; hg19: chr3-70016904;