chr3-69951805-T-A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). BP4BP6

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 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 ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -2 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
• BP6: ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 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>A		splice_region intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_000248.4	MANE Plus Clinical	c.560-7T>A		splice_region intron	N/A	NP_000239.1	O75030-9
	MITF	NM_001354605.2		c.878-7T>A		splice_region 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.881-7T>A		splice_region intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000394351.9	TSL:1 MANE Plus Clinical	c.560-7T>A		splice_region intron	N/A	ENSP00000377880.3	O75030-9
	MITF	ENST00000314557.10	TSL:1	c.560-25T>A		intron	N/A	ENSP00000324246.6	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	0.000381	58	0	152214	31
GnomAD2 exomes	0.000327	82		250564
GnomAD4 exome	0.000492	719	0	1460072	30
GnomAD4 genome	0.000381	58	0	152214	31
TOPMed (Bravo)	0.000351	93	0	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.000504	24	0	47580
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	0.000461	6		13006
UK10K	0.00106	8		7562

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 prediction	Prediction	Score
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	polymorphism	97/3
PhyloP100	Benign	-	3.6

Showing 9 of 9 scores

Splicing Scores

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

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.

Other links and lift over

dbSNP: rs200580325;

hg19: chr3-70000956;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar