rs1553704814

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_001354604.2(MITF):c.970_972delAGA(p.Arg324del) variant causes a conservative 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 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Tietz syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics
Waardenburg syndrome type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Waardenburg syndrome type 2A
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
melanoma, cutaneous malignant, susceptibility to, 8
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Waardenburg syndrome
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Waardenburg-Shah syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MITF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 VariationId is 14272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2 link	c.970_972delAGA	p.Arg324del	conservative_inframe_deletion	Exon 8 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4 link	c.649_651delAGA	p.Arg217del	conservative_inframe_deletion	Exon 7 of 9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9 link	c.970_972delAGA	p.Arg324del	conservative_inframe_deletion	Exon 8 of 10	1	NM_001354604.2	ENSP00000295600.8		O75030-1
MITF	ENST00000394351.9 link	c.649_651delAGA	p.Arg217del	conservative_inframe_deletion	Exon 7 of 9	1	NM_000248.4	ENSP00000377880.3		O75030-9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460656

Hom.:

AF XY:

0.00

AC XY:

AN XY:

726704

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111040

Other (OTH)

AF:

0.00

AC:

AN:

60354

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tietz syndrome

Pathogenic:3

Jul 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

Pathogenic:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.649_651del, results in the deletion of 1 amino acid(s) of the MITF protein (p.Arg217del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Waardenburg syndrome, type 2A (PMID: 20478267, 29094203, 34142234). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14272). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Feb 09, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Waardenburg syndrome

Pathogenic:1

Mar 01, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 01, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over