chr3-69964940-G-A

Variant names:

• chr3-69964940-G-A
• rs149617956
• NM_001354604.2:c.1273G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 12P and 6B. PS3 PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_001354604.2(MITF):​c.1273G>A​(p.Glu425Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,114 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,risk factor (★★). ClinVar reports functional evidence for this variant: "SCV000696089: Experimental evidence suggests that this missense change causes decreased SUMOylation of MITF, resulting in an increased transcriptional activity with enhanced migration, invasion and colony formation in stable melanoma cells (Bertolotto_2011)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:27 O:5
• Conservation: PhyloP100: 8.01
• Publications: 238 publications found

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, Ambry Genetics, Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Waardenburg syndrome type 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000696089: Experimental evidence suggests that this missense change causes decreased SUMOylation of MITF, resulting in an increased transcriptional activity with enhanced migration, invasion and colony formation in stable melanoma cells (Bertolotto_2011).; SCV004046260: Experimental studies have shown that the p.Glu419Lys variant leads to abnormal transcription of target genes and, in certain cell lines, increased colony forming potential (PMID: 22012259, 22080950, 23787126).; SCV004801538: Functional analysis showed that MITF encoded by the p.(Glu318Lys) variant allele had impaired sumoylation and differentially regulated several MITF targets. Berwick et al. (2014); SCV000184481: Functional analysis suggests that this variant prevents appropriate sumoylation, which leads to differential binding and activation of MITF target genes (Yokoyama S et al. Nature. 2011 Dec;480:99-103; Grill C et al. Hum. Mol. Genet. 2013 Nov;22:4357-67).; SCV000684704: Functional studies have shown that this variant decreases the SUMOylation of MITF, resulting in altered transcription of target genes and increased colony forming potential (PMID: 22012259, 22080950, 28376192).; SCV006324484: Functional analyses of p.E318K have shown that it impairs sumoylation and alters MITF transcriptional activity in transfected melanoma cell lines (PMID: 22080950, 22012259, 23787126).; SCV000568597: Published functional studies demonstrate a damaging effect: impaired sumoylation and differentially regulated expression of several MITF target genes (Bertolotto 2011, Yokoyama 2011, Grill 2013, Bonet 2017); PMID: 23787126, 27473757, 28125078, 28825054, 31034483, 22012259, 22080950, 28376192, 23167872, 24767713, 25803691, 26650189, 23774529, 24406078, 27153395, 27680874, 26800492, 27181379, 26775776, 26999813, 26999650, 27899189, 27720647, 28787086, 28152038, 24660985, 24290354, 23802662, 23046018, 22158021, 2440678, 24352080, 29485552, 29706638, 29506128, 30759220, 31201024, 30414346, 32054529, 31465090, 33240314; SCV002774816: In addition, functional studies have shown that this variant causes MITF protein overactivity (PMIDs: 22012259 (2011), 22080950 (2011), and 23787126 (2013)).; SCV004563072: "In vitro and in vivo functional analyses demonstrate the glutamic acid to lysine amino acid change results in defective SUMOylation of the MITF protein causing defective cellular senescence (Bertolotto 2011, Bonet 2017)." PMID: 22012259; SCV000283992: Experimental studies have shown that this missense change affects MITF function (PMID: 22012259, 22080950, 23787126).; SCV005900649: Experimental studies have shown that this missense change decreases the SUMOylation of MITF, leading to elevated transcription of target genes and increased colony forming potential in certain cell lines (PMID: 22012259, 22080950, 23787126).
• PP5: Variant 3-69964940-G-A is Pathogenic according to our data. Variant chr3-69964940-G-A is described in ClinVar as Pathogenic/Likely_pathogenic|risk_factor. ClinVar VariationId is 29792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.034677655). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (240/152232) while in subpopulation NFE AF = 0.00244 (166/68008). AF 95% confidence interval is 0.00214. There are 1 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354604.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.1273G>A	p.Glu425Lys	missense	Exon 10 of 10	NP_001341533.1	O75030-1
	MITF	NM_000248.4	MANE Plus Clinical	c.952G>A	p.Glu318Lys	missense	Exon 9 of 9	NP_000239.1	O75030-9
	MITF	NM_001354605.2		c.1270G>A	p.Glu424Lys	missense	Exon 10 of 10	NP_001341534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.1273G>A	p.Glu425Lys	missense	Exon 10 of 10	ENSP00000295600.8	O75030-1
	MITF	ENST00000394351.9	TSL:1 MANE Plus Clinical	c.952G>A	p.Glu318Lys	missense	Exon 9 of 9	ENSP00000377880.3	O75030-9
	MITF	ENST00000314557.10	TSL:1	c.934G>A	p.Glu312Lys	missense	Exon 9 of 9	ENSP00000324246.6	O75030-10

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00136 AC: 342 AN: 251388 AF XY: 0.00135

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00291 AC: 4251 AN: 1461882 Hom.: 9 Cov.: 31 AF XY: 0.00273 AC XY: 1983 AN XY: 727244

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00362 AC: 4030 AN: 1112004

Other (OTH) AF: 0.00215 AC: 130 AN: 60396

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74420

African (AFR) AF: 0.000818 AC: 34 AN: 41544

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00244 AC: 166 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00227 Hom.: 6

Bravo AF: 0.00179

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.00278

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Melanoma, cutaneous malignant, susceptibility to, 8 (10)
8	-	-	not provided (9)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	Familial melanoma (2)
1	-	-	MITF-related disorder (1)
1	-	-	Tietz syndrome (1)
1	-	-	Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 (1)
1	-	-	Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8;C4310625:Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (1)
-	-	-	Melanoma (1)
-	-	-	not specified (1)
-	-	-	Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.035	T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.44
Sift	Benign	0.039	D
Sift4G	Benign	0.081	T
Polyphen		0.98	D
Vest4		0.81
MVP		0.76
MPC		1.0
ClinPred		0.049	T
GERP RS		6.2
Varity_R		0.44
gMVP		0.52
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs149617956; hg19: chr3-70014091; COSMIC: COSV108119547;