rs1553704814

Positions:

• chr3-69956460-CGAA-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001354604.2(MITF):​c.970_972del​(p.Arg324del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MITF NM_001354604.2 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001354604.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001354604.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-69956460-CGAA-C is Pathogenic according to our data. Variant chr3-69956460-CGAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 14272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69956460-CGAA-C is described in Lovd as [Pathogenic]. Variant chr3-69956460-CGAA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_000248.4	c.649_651del	p.Arg217del	inframe_deletion	7/9	ENST00000394351.9
MITF	NM_001354604.2	c.970_972del	p.Arg324del	inframe_deletion	8/10	ENST00000352241.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.970_972del	p.Arg324del	inframe_deletion	8/10	1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.649_651del	p.Arg217del	inframe_deletion	7/9	1	NM_000248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460656 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tietz syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. The variant leading to inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23787126). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 22258527). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000014272/ PMID: 8589691). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2023

Observed in other patients with Waardenburg syndrome in published literature (Chen et al., 2010; Shi et al., 2016); Published functional studies demonstrate a damaging effect on DNA binding (Grill et al., 2013; Wang et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 22258527, 20485200, 29094203, 27889061, 20478267, 23787126, 24194866, 8589691, 29531335, 30978479, 27604145, 26781036, 26663054, 29938923, 8622664, 29115496, 27073475, 32005694, 34142234) -

Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

Waardenburg syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2019

The p.Arg217del variant in MITF is an in-frame deletion of an arginine and has been reported in >10 individuals with type 2 Waardenburg/Tietz syndrome, including at least 2 individuals who were apparently de novo without maternity and paternity confirmation (Chen 2010, Chen 2016, Hai 2017, Leger 2012, Shi 2016, Shigemura 2010, Tassabehji 1995, Wang 2018, Yang 2013). One individual with COMMAD syndrome has also been described (George 2016). The variant segregated in 9 affected family members, including the two family members of the proband with COMMAD syndrome who had Waardenburg syndrome (George 2016). In vitro functional studies have shown that the p.Arg217del results in inability of MITF to bind DNA and activate melanocyte-specific promotors, and the p.Arg217del variant represents the mouse equivalent mutation in the microphthalmia mi/mi mouse (George 2016, Grill 2013, Shigemura 2010, Wang 2018, Tassabehji 1995). This variant was absent from large population studies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant type 2 Waardenburg/Tietz syndrome based on the evidence outlined above. ACMG/AMP criteria applied: PS3, PS4, PM6_Strong, PP1_Strong, PM2, PP4, PM4_Supporting. -

Waardenburg syndrome type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553704814; hg19: chr3-70005611;