3-69763911-A-G

Position:

• chr3-69763911-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_006722.3(MITF):​c.70A>G​(p.Arg24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000409 in 1,222,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MITF NM_006722.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.293

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06777024).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.104+24210A>G		intron_variant		ENST00000352241.9	NP_001341533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.104+24210A>G		intron_variant		1	NM_001354604.2	ENSP00000295600.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000409 AC: 5 AN: 1222380 Hom.: 0 Cov.: 31 AF XY: 0.00000666 AC XY: 4 AN XY: 600648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000297

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000417

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MITF-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2023

The MITF c.70A>G variant is predicted to result in the amino acid substitution p.Arg24Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0034% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-69813062-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.96
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.018
Sift	Benign	0.14	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0	.;B
Vest4		0.10
MutPred		0.32		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.12
ClinPred		0.040	T
GERP RS		2.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1335773753; hg19: chr3-69813062;