chr3-69763693-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001354604.2(MITF):​c.104+23992G>T variant causes a intron change. The variant allele was found at a frequency of 0.00175 in 1,298,072 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 21 hom., cov: 33)
Exomes 𝑓: 0.00081 ( 15 hom. )

Consequence

MITF
NM_001354604.2 intron

Scores

1
1
Splicing: ADA: 0.8492
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.88
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
Variant 3-69763693-G-T is Benign according to our data. Variant chr3-69763693-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 669675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1343/152336) while in subpopulation AFR AF= 0.0312 (1299/41574). AF 95% confidence interval is 0.0298. There are 21 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1343 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MITFNM_001354604.2 linkuse as main transcriptc.104+23992G>T intron_variant ENST00000352241.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MITFENST00000352241.9 linkuse as main transcriptc.104+23992G>T intron_variant 1 NM_001354604.2 P4O75030-1

Frequencies

GnomAD3 genomes
AF:
0.00881
AC:
1341
AN:
152218
Hom.:
22
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0313
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00209
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00334
GnomAD4 exome
AF:
0.000810
AC:
928
AN:
1145736
Hom.:
15
Cov.:
31
AF XY:
0.000772
AC XY:
428
AN XY:
554440
show subpopulations
Gnomad4 AFR exome
AF:
0.0332
Gnomad4 AMR exome
AF:
0.00118
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000950
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000192
Gnomad4 OTH exome
AF:
0.00172
GnomAD4 genome
AF:
0.00882
AC:
1343
AN:
152336
Hom.:
21
Cov.:
33
AF XY:
0.00882
AC XY:
657
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.0312
Gnomad4 AMR
AF:
0.00209
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00473
Hom.:
5
Bravo
AF:
0.0101
Asia WGS
AF:
0.00144
AC:
6
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024MITF: BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 12, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
CADD
Pathogenic
28
DANN
Uncertain
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.85
dbscSNV1_RF
Benign
0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72950037; hg19: chr3-69812844; API