rs1478130504

Variant names:

• chr3-69879246-C-G
• rs1478130504
• NM_001354604.2:c.217C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-69879246-C-G
• chr3-69879246-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001354604.2(MITF):​c.217C>G​(p.Arg73Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• Publications: 8 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, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2	c.217C>G	p.Arg73Gly	missense_variant	Exon 2 of 10	ENST00000352241.9	NP_001341533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.217C>G	p.Arg73Gly	missense_variant	Exon 2 of 10	1	NM_001354604.2	ENSP00000295600.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;.;.;T;.;T;.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.;.;.;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;.;D;D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;.;D;D;D;D;D;D;T
Polyphen		1.0	D;.;D;.;.;.;.;D;D;.
Vest4		0.77
MVP		0.65
MPC		0.97
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.62
gMVP		0.81
Mutation Taster		=52/48	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1478130504; hg19: chr3-69928397;