3-69956130-A-G

Variant names:

• chr3-69956130-A-G
• rs7623610
• NM_001354604.2:c.956-325A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354604.2(MITF):​c.956-325A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 152,060 control chromosomes in the GnomAD database, including 33,975 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (33975 hom., cov: 32)
• Consequence: MITF NM_001354604.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.61
• Publications: 15 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: Ambry Genetics, G2P, 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• melanoma, cutaneous malignant, susceptibility to, 8

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

  Inheritance: AR Classification: STRONG Submitted by: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

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.956-325A>G		intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_000248.4	MANE Plus Clinical	c.635-325A>G		intron	N/A	NP_000239.1	O75030-9
	MITF	NM_001354605.2		c.953-325A>G		intron	N/A	NP_001341534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.956-325A>G		intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000394351.9	TSL:1 MANE Plus Clinical	c.635-325A>G		intron	N/A	ENSP00000377880.3	O75030-9
	MITF	ENST00000314557.10	TSL:1	c.617-325A>G		intron	N/A	ENSP00000324246.6	O75030-10

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98482 AN: 151942 Hom.: 33918 Cov.: 32

Gnomad AFR AF: 0.903

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.648 AC: 98600 AN: 152060 Hom.: 33975 Cov.: 32 AF XY: 0.644 AC XY: 47858 AN XY: 74296

African (AFR) AF: 0.903 AC: 37489 AN: 41518

American (AMR) AF: 0.612 AC: 9354 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1991 AN: 3470

East Asian (EAS) AF: 0.535 AC: 2757 AN: 5150

South Asian (SAS) AF: 0.622 AC: 2996 AN: 4818

European-Finnish (FIN) AF: 0.496 AC: 5220 AN: 10532

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36874 AN: 67976

Other (OTH) AF: 0.602 AC: 1271 AN: 2112

Alfa AF: 0.576 Hom.: 57174

Bravo AF: 0.669

Asia WGS AF: 0.647 AC: 2252 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.33
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7623610;

hg19: chr3-70005281;