rs200580325

chr3-69951805-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

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:4 B:1
• Conservation: PhyloP100: 3.62

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 Likely_benign. Variant got -6 ACMG points.

• BP4: 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. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_000248.4	c.560-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394351.9
MITF	NM_001354604.2	c.881-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000352241.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.881-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.560-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000248.4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152214 Hom.: 0 Cov.: 31

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: 82 AN: 250564 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135416

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.: 0 Cov.: 30 AF XY: 0.000465 AC XY: 338 AN XY: 726432

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: 58 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74360

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.: 0

Bravo AF: 0.000351

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.10
Cadd	Benign	18
Dann	Benign	0.94

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

Other links and lift over

dbSNP: rs200580325; hg19: chr3-70000956;