3-69951805-T-A

Position:

chr3-69951805-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_001354604.2(MITF):c.881-7T>A variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000482 in 1,612,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

MITF
NM_001354604.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.2684

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.1).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000381 (58/152214) while in subpopulation NFE AF= 0.000735 (50/68030). AF 95% confidence interval is 0.000572. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_000248.4 linkuse as main transcript	c.560-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394351.9	NP_000239.1
MITF	NM_001354604.2 linkuse as main transcript	c.881-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, 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.881-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001354604.2	ENSP00000295600	P4	O75030-1
MITF	ENST00000394351.9 linkuse as main transcript	c.560-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000248.4	ENSP00000377880		O75030-9

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000327

AC:

AN:

250564

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000628

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000492

AC:

719

AN:

1460072

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

338

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000615

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.000381

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000491

Hom.:

Bravo

AF:

0.000351

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 25, 2016	The c.560-7T>A variant in MITF has now been identified by our laboratory in two individuals with hearing loss, but one of them had an alternate genetic etiology to explain the hearing loss. This variant has also been identified in 0.05% (30 /64734) of European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs200580325). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. This variant is located in the 3' splice region. Computational too ls suggest a possible impact to splicing. However, this information is not predi ctive enough to determine pathogenicity. In summary, the clinical significance o f the c.560-7T>A variant is uncertain. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2022	In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.94

BranchPoint Hunter

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.27

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: 7

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