Variant 3-69763693-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBS1BS2

The NM_001184967.2(MITF):c.-53+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00175 in 1,298,072 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 21 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 15 hom. )

Consequence

MITF
NM_001184967.2 splice_donor, intron

Scores

Splicing: ADA: 0.8492

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.88

Variant links:

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 links:

MITF (HGNC:):

MITF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13361762 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of 35, new splice context is: ttgGTcagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 3-69763693-G-T is Benign according to our data. Variant chr3-69763693-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 669675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1343/152336) while in subpopulation AFR AF= 0.0312 (1299/41574). AF 95% confidence interval is 0.0298. There are 21 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2 linkuse as main transcript	c.104+23992G>T		intron_variant		ENST00000352241.9	NP_001341533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9 linkuse as main transcript	c.104+23992G>T		intron_variant		1	NM_001354604.2	ENSP00000295600.8		O75030-1

Frequencies

GnomAD3 genomes

AF:

0.00881

AC:

1341

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00334

GnomAD4 exome

AF:

0.000810

AC:

928

AN:

1145736

Hom.:

Cov.:

AF XY:

0.000772

AC XY:

428

AN XY:

554440

show subpopulations

Gnomad4 AFR exome

AF:

0.0332

Gnomad4 AMR exome

AF:

0.00118

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000950

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000192

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00882

AC:

1343

AN:

152336

Hom.:

Cov.:

AF XY:

0.00882

AC XY:

657

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0312

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00473

Hom.:

Bravo

AF:

0.0101

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MITF: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Benign

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over