rs779387274

Positions:

• chr3-69866298-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001354604.2(MITF):​c.105-12836C>T variant causes a intron change. The variant allele was found at a frequency of 0.0000192 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MITF NM_001354604.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.67

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15411964).
• BP6: Variant 3-69866298-C-T is Benign according to our data. Variant chr3-69866298-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227547.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_001354604.2	c.105-12836C>T		intron_variant		ENST00000352241.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.105-12836C>T		intron_variant		1	NM_001354604.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 248930 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135070

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461442 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 29, 2015

p.Ala3Val in exon 01c of MITF: This variant is not expected to have clinical si gnificance because the alanine (Ala) residue at position 3 is not conserved thro ugh species, with Egyptian jerboa, elephant and Cape elephant shrew all having a valine (Val) at this position. Additional computational analyses suggest that this variant may not impact the protein. It has been identified in 1/66732 Eur opean chromosomes and 1/16512 South Asian chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.89
Eigen	Benign	0.015
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;N
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.067
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.20	B;.
Vest4		0.41
MutPred		0.36		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.30
ClinPred		0.15	T
GERP RS		5.8

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs779387274; hg19: chr3-69915449;