3-69739945-C-A

Variant names:

• chr3-69739945-C-A
• rs45519135
• NM_001354604.2:c.104+244C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001354604.2(MITF):​c.104+244C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 152,168 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.021 (46 hom., cov: 32)
• Consequence: MITF NM_001354604.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.524
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-69739945-C-A is Benign according to our data. Variant chr3-69739945-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1197772.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0211 (3205/152168) while in subpopulation NFE AF = 0.0331 (2247/67986). AF 95% confidence interval is 0.0319. There are 46 homozygotes in GnomAd4. There are 1452 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 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.104+244C>A		intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_001354605.2		c.104+244C>A		intron	N/A	NP_001341534.1
	MITF	NM_198159.3		c.104+244C>A		intron	N/A	NP_937802.1	O75030-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.104+244C>A		intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000956046.1		c.104+244C>A		intron	N/A	ENSP00000626105.1
	MITF	ENST00000956043.1		c.104+244C>A		intron	N/A	ENSP00000626102.1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3208 AN: 152050 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0278

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

GnomAD4 genome AF: 0.0211 AC: 3205 AN: 152168 Hom.: 46 Cov.: 32 AF XY: 0.0195 AC XY: 1452 AN XY: 74382

African (AFR) AF: 0.00623 AC: 259 AN: 41554

American (AMR) AF: 0.0157 AC: 240 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00997 AC: 48 AN: 4814

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10616

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0331 AC: 2247 AN: 67986

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0247 Hom.: 9

Bravo AF: 0.0213

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.77
PhyloP100		0.52
PromoterAI		0.068	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs45519135; hg19: chr3-69789096;