rs104893746

Positions:

• chr3-69956460-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001354604.2(MITF):​c.961C>T​(p.Arg321*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MITF NM_001354604.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.297

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-69956460-C-T is Pathogenic according to our data. Variant chr3-69956460-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69956460-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.961C>T	p.Arg321*	stop_gained	8/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.640C>T	p.Arg214*	stop_gained	7/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.961C>T	p.Arg321*	stop_gained	8/10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.640C>T	p.Arg214*	stop_gained	7/9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460658 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726708

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 2A Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000014276 / PMID: 8659547). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 14, 2017	A heterozygous nonsense variant was identified, NM_000248.3(MITF):c.640C>T in exon 7 of MITF. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 214, NP_000239.1(MITF):p.(Arg214*). This is predicted to result in loss of protein function either through truncation (half of the protein, including a helix-loop-helix domain and a MiT/TRFE transcription factor domain) or nonsense-mediated decay. This variant is not present in the gnomAD population database. It has been previously reported as a pathogenic variant in patients with Waardenburg syndrome (ClinVar). In addition, functional studies show that this variant causes loss of DNA binding activity and failure of transcription activity (Nobukuni. et al., (1996)). Other truncating variants downstream of c.640C>T in MITF have also been reported as pathogenic in individuals with Waardenburg syndrome. Subsequent testing of this patients parents indicates the variant is due to a de novo event. Based on current information, this variant has been classified as PATHOGENIC. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 04, 1998	- -
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	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect due to inhibition of DNA binding and subsequent promoter activation (Nobukuni et al., 1996; Grill et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23787126, 25525159, 9856573, 29293505, 31827275, 8659547, 31850270, 33297549, 32422366) -

Poliosis;C0423318:Heterochromia iridis;C4021806:Prelingual sensorineural hearing impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 27, 2014

- -

Hearing impairment Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 10, 2016

- -

Ear malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.98
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.7

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: rs104893746; hg19: chr3-70005611; COSMIC: COSV58832470;