rs12247015

Variant names:

• chr10-58385319-A-G
• rs12247015
• NM_003201.3:c.-229A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003201.3(TFAM):​c.-229A>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 NM_003201.3 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.03
• Publications: 22 publications found

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]

TFAM Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 15 (hepatocerebral type)

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 684177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
TFAM	NM_003201.3	c.-229A>G		upstream_gene_variant		ENST00000487519.6	NP_003192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAM	ENST00000487519.6	c.-229A>G		upstream_gene_variant		1	NM_003201.3	ENSP00000420588.1
TFAM	ENST00000373895.7	c.-229A>G		upstream_gene_variant		2		ENSP00000363002.3
TFAM	ENST00000373899.3	n.-26A>G		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

African (AFR) AF: 0.747 AC: 9713 AN: 13000

American (AMR) AF: 0.319 AC: 7776 AN: 24362

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 7157 AN: 14260

East Asian (EAS) AF: 0.182 AC: 5439 AN: 29826

South Asian (SAS) AF: 0.321 AC: 16072 AN: 50112

European-Finnish (FIN) AF: 0.318 AC: 8833 AN: 27762

Middle Eastern (MID) AF: 0.452 AC: 895 AN: 1982

European-Non Finnish (NFE) AF: 0.425 AC: 113127 AN: 266244

Other (OTH) AF: 0.419 AC: 10785 AN: 25762

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

African (AFR) AF: 0.754 AC: 31308 AN: 41536

American (AMR) AF: 0.381 AC: 5829 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1704 AN: 3470

East Asian (EAS) AF: 0.175 AC: 901 AN: 5156

South Asian (SAS) AF: 0.297 AC: 1427 AN: 4810

European-Finnish (FIN) AF: 0.318 AC: 3368 AN: 10598

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28908 AN: 67970

Other (OTH) AF: 0.484 AC: 1019 AN: 2106

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.0
PromoterAI		-0.089	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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