Genetic Variant NM_001354604.2:c.956-325A>G (chr3-69956130-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.61

Publications

15 publications found

Variant links:

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, Orphanet, Ambry Genetics
Waardenburg syndrome type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Waardenburg syndrome type 2A
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
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: PanelApp Australia, 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

MITF links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2 link	c.956-325A>G		intron_variant	Intron 7 of 9	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4 link	c.635-325A>G		intron_variant	Intron 6 of 8	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9 link	c.956-325A>G		intron_variant	Intron 7 of 9	1	NM_001354604.2	ENSP00000295600.8		O75030-1
MITF	ENST00000394351.9 link	c.635-325A>G		intron_variant	Intron 6 of 8	1	NM_000248.4	ENSP00000377880.3		O75030-9

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98482

AN:

151942

Hom.:

33918

Cov.:

show subpopulations

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.:

AF XY:

0.644

AC XY:

47858

AN XY:

74296

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1556

3112

4667

6223

7779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.13

(source)

DANN

Benign

0.33

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over