3-69951805-T-A

Variant names:

• chr3-69951805-T-A
• rs200580325
• NM_001354604.2:c.881-7T>A

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O6_Supporting

The NM_001354604.2(MITF):c.881-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The gene MITF is a known oncogene (CancerMine: 5 TSG, 218 oncogene, 40 driver citations). The gene MITF is a cancer driver gene (CancerMine: 5 TSG, 218 oncogene, 40 driver citations). The variant allele was found at a cumulative frequency of 0.000482 (AC=777) in the gnomAD database across 1,612,286 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000576. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: MITF NM_001354604.2 splice_region, intron
• Scores: Splicing: ADA: 0.2684
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.62
• Publications: 2 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, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Splice-region variant — splicing algorithms predict an impact on splicing; supports O6

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MITF NM_001354604.2	MANE Select	c.881-7T>A	splice_regionintron	Intron 6 of 9	Prot: NP_001341533.1 UniProt:
	MITF NM_000248.4	MANE Plus Clinical	c.560-7T>A	splice_regionintron	Intron 5 of 8	Prot: NP_000239.1 UniProt:
	MITF NM_001354605.2		c.878-7T>A	splice_regionintron	Intron 6 of 9	Prot: NP_001341534.1

MITF NM_001354604.2

MANE Select

HGVSc / HGVSpc.881-7T>A

Exon rankIntron 6 of 9

splice_regionintron

Prot: NP_001341533.1UniProt: O75030-1

MITF NM_000248.4

MANE Plus Clinical

HGVSc / HGVSpc.560-7T>A

Exon rankIntron 5 of 8

splice_regionintron

Prot: NP_000239.1UniProt: O75030-9

MITF NM_001354605.2

HGVSc / HGVSpc.878-7T>A

Exon rankIntron 6 of 9

splice_regionintron

Prot: NP_001341534.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MITF ENST00000352241.9	TSL:1MANE Select	c.881-7T>A	splice_regionintron	Intron 6 of 9	Prot: ENSP00000295600.8 UniProt:
	MITF ENST00000394351.9	TSL:1MANE Plus Clinical	c.560-7T>A	splice_regionintron	Intron 5 of 8	Prot: ENSP00000377880.3 UniProt:
	MITF ENST00000314557.10	TSL:1	c.560-25T>A	intron	Intron 5 of 8	Prot: ENSP00000324246.6 UniProt:

MITF ENST00000352241.9

TSL:1MANE Select

HGVSc / HGVSpc.881-7T>A

Exon rankIntron 6 of 9

splice_regionintron

Prot: ENSP00000295600.8UniProt: O75030-1

MITF ENST00000394351.9

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.560-7T>A

Exon rankIntron 5 of 8

splice_regionintron

Prot: ENSP00000377880.3UniProt: O75030-9

MITF ENST00000314557.10

TSL:1

HGVSc / HGVSpc.560-25T>A

Exon rankIntron 5 of 8

intron

Prot: ENSP00000324246.6UniProt: O75030-10

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000381	AC:58	Hom:0	AN:152214	Cov:31
GnomAD2 exomes	AF: 0.000327	AC:82	Hom:	AN:250564	Cov:
GnomAD4 exome	AF: 0.000492	AC:719	Hom:0	AN:1460072	Cov:30
GnomAD4 genome	AF: 0.000381	AC:58	Hom:0	AN:152214	Cov:31
TOPMed (Bravo)	AF: 0.000351	AC:93	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000504	AC:24	Hom:0	AN:47580	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000461	AC:6	Hom:	AN:13006	Cov:
UK10K	AF: 0.00106	AC:8	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	1488	0.000278 *	2	7184
BipEx(Bipolar disorder (including schizoaffective))	0.000422	12	28418	0.000693	20	28844
SCHEMA(Schizophrenia)	0.000279	34	121836	0.000325	62	190588

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	not specified (2)
-	1	-	Melanoma, cutaneous malignant, susceptibility to, 8 (1)
-	-	1	Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
BayesDel_noAF	Benign	-0.10
BranchPoint Hunter	N/A	3.0
CADD	Benign	18
DANN	Benign	0.94
GPN-Star LLR	N/A	-8.1
GPN-Star score	N/A	8.1
Mutation Taster	N/A	97/3	polymorphism
PhyloP100	Benign	3.6

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.44
DS_AL_spliceai	Uncertain	0.21	Position offset: 7
Pangolin (max)	Benign	0.16
Pangolin loss	Benign	0.16	Position offset: 7
SpliceAI score (max)	Uncertain	0.21	Details are displayed if max score is > 0.2

Showing 6 of 6 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200580325;

hg19: chr3-70000956;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar