3-69951805-T-C

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4BP6_Moderate

The NM_001354604.2(MITF):c.881-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000685 (AC=1) in the gnomAD database across 1,460,078 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MITF NM_001354604.2 splice_region, intron
• Scores: Splicing: ADA: 0.1196
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.62
• 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, 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000116 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00278) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

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>C	splice_regionintron	Intron 6 of 9	Prot: NP_001341533.1 UniProt:
	MITF NM_000248.4	MANE Plus Clinical	c.560-7T>C	splice_regionintron	Intron 5 of 8	Prot: NP_000239.1 UniProt:
	MITF NM_001354605.2		c.878-7T>C	splice_regionintron	Intron 6 of 9	Prot: NP_001341534.1

MITF NM_001354604.2

MANE Select

HGVSc / HGVSpc.881-7T>C

Exon rankIntron 6 of 9

splice_regionintron

Prot: NP_001341533.1UniProt: O75030-1

MITF NM_000248.4

MANE Plus Clinical

HGVSc / HGVSpc.560-7T>C

Exon rankIntron 5 of 8

splice_regionintron

Prot: NP_000239.1UniProt: O75030-9

MITF NM_001354605.2

HGVSc / HGVSpc.878-7T>C

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>C	splice_regionintron	Intron 6 of 9	Prot: ENSP00000295600.8 UniProt:
	MITF ENST00000394351.9	TSL:1MANE Plus Clinical	c.560-7T>C	splice_regionintron	Intron 5 of 8	Prot: ENSP00000377880.3 UniProt:
	MITF ENST00000314557.10	TSL:1	c.560-25T>C	intron	Intron 5 of 8	Prot: ENSP00000324246.6 UniProt:

MITF ENST00000352241.9

TSL:1MANE Select

HGVSc / HGVSpc.881-7T>C

Exon rankIntron 6 of 9

splice_regionintron

Prot: ENSP00000295600.8UniProt: O75030-1

MITF ENST00000394351.9

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.560-7T>C

Exon rankIntron 5 of 8

splice_regionintron

Prot: ENSP00000377880.3UniProt: O75030-9

MITF ENST00000314557.10

TSL:1

HGVSc / HGVSpc.560-25T>C

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF: 6.85e-7	AC:1	Hom:0	AN:1460078	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	20
BayesDel_noAF	Benign	-0.13
BranchPoint Hunter	N/A	3.0
CADD	Benign	17
DANN	Benign	0.93
GPN-Star LLR	N/A	-6.9
GPN-Star score	N/A	6.9
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	0.12
dbscSNV1_RF	Benign	0.46
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 4 of 4 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