rs12247015

Positions:

• chr10-58385319-A-G
• chr10-58385319-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The 10-58385319-A-G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 605,450 control chromosomes in the GnomAD database, including 59,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (20812 hom., cov: 33)
  • Exomes 𝑓: 0.40 (38350 hom.)
• Consequence: TFAM ENST00000373899.3 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

Genes affected

TFAM (HGNC:11741): (transcription factor A, mitochondrial) This gene encodes a key mitochondrial transcription factor containing two high mobility group motifs. The encoded protein also functions in mitochondrial DNA replication and repair. Sequence polymorphisms in this gene are associated with Alzheimer's and Parkinson's diseases. There are pseudogenes for this gene on chromosomes 6, 7, and 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-58385319-A-G is Benign according to our data. Variant chr10-58385319-A-G is described in ClinVar as [Benign]. Clinvar id is 684177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFAM	ENST00000373899.3			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 75019 AN: 152022 Hom.: 20792 Cov.: 33

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.397 AC: 179797 AN: 453310 Hom.: 38350 Cov.: 2 AF XY: 0.393 AC XY: 94647 AN XY: 240946

Gnomad4 AFR exome AF: 0.747

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.502

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.425

Gnomad4 OTH exome AF: 0.419

GnomAD4 genome AF: 0.494 AC: 75083 AN: 152140 Hom.: 20812 Cov.: 33 AF XY: 0.482 AC XY: 35840 AN XY: 74364

Gnomad4 AFR AF: 0.754

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.491

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.484

Alfa AF: 0.357 Hom.: 1368

Bravo AF: 0.511

Asia WGS AF: 0.237 AC: 826 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This 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	-0.85
CADD	Benign	2.1
DANN	Benign	0.62

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

LitVar

Other links and lift over

dbSNP: rs12247015; hg19: chr10-60145079; COSMIC: COSV65877353; COSMIC: COSV65877353;