chr3-69959310-T-C

Position:

• chr3-69959310-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The ENST00000352241.9(MITF):​c.1069T>C​(p.Ser357Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S357Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF ENST00000352241.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain bHLH (size 53) in uniprot entity MITF_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in ENST00000352241.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-69959311-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1202629.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 3-69959310-T-C is Pathogenic according to our data. Variant chr3-69959310-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 14273.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-69959310-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.1069T>C	p.Ser357Pro	missense_variant	9/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.748T>C	p.Ser250Pro	missense_variant	8/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.1069T>C	p.Ser357Pro	missense_variant	9/10	1	NM_001354604.2	ENSP00000295600	P4
MITF	ENST00000394351.9	c.748T>C	p.Ser250Pro	missense_variant	8/9	1	NM_000248.4	ENSP00000377880

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Waardenburg syndrome type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;.;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.;D;D;.
Vest4		1.0
MutPred		0.67		Loss of stability (P = 0.0573);.;Loss of stability (P = 0.0573);.;.;.;.;.;.;.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs104893744; hg19: chr3-70008461;