10-58388932-A-G

Variant names:

• chr10-58388932-A-G
• rs2306604
• NM_003201.3:c.441+113A>G

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.441+113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 974,548 control chromosomes in the GnomAD database, including 106,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23180 hom., cov: 33)
  • Exomes 𝑓: 0.45 (82999 hom.)
• Consequence: TFAM NM_003201.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.504
• Publications: 42 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=-0.9).
• BP6: Variant 10-58388932-A-G is Benign according to our data. Variant chr10-58388932-A-G is described in ClinVar as Benign. ClinVar VariationId is 684189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003201.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	NM_003201.3	MANE Select	c.441+113A>G		intron	N/A	NP_003192.1
	TFAM	NM_001270782.2		c.441+113A>G		intron	N/A	NP_001257711.1
	TFAM	NR_073073.2		n.646+113A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	ENST00000487519.6	TSL:1 MANE Select	c.441+113A>G		intron	N/A	ENSP00000420588.1
	TFAM	ENST00000395377.2	TSL:2	c.384+113A>G		intron	N/A	ENSP00000378776.2
	TFAM	ENST00000373895.7	TSL:2	c.441+113A>G		intron	N/A	ENSP00000363002.3

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80253 AN: 151972 Hom.: 23156 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.519

GnomAD4 exome AF: 0.446 AC: 366532 AN: 822460 Hom.: 82999 AF XY: 0.445 AC XY: 188845 AN XY: 424692

African (AFR) AF: 0.789 AC: 15504 AN: 19642

American (AMR) AF: 0.409 AC: 11148 AN: 27244

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 9717 AN: 18712

East Asian (EAS) AF: 0.495 AC: 16566 AN: 33478

South Asian (SAS) AF: 0.427 AC: 26015 AN: 60966

European-Finnish (FIN) AF: 0.359 AC: 10703 AN: 29790

Middle Eastern (MID) AF: 0.476 AC: 1320 AN: 2774

European-Non Finnish (NFE) AF: 0.436 AC: 258074 AN: 591926

Other (OTH) AF: 0.461 AC: 17485 AN: 37928

GnomAD4 genome AF: 0.528 AC: 80326 AN: 152088 Hom.: 23180 Cov.: 33 AF XY: 0.520 AC XY: 38658 AN XY: 74342

African (AFR) AF: 0.781 AC: 32384 AN: 41486

American (AMR) AF: 0.444 AC: 6783 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1746 AN: 3470

East Asian (EAS) AF: 0.491 AC: 2536 AN: 5168

South Asian (SAS) AF: 0.411 AC: 1983 AN: 4822

European-Finnish (FIN) AF: 0.345 AC: 3657 AN: 10588

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29500 AN: 67944

Other (OTH) AF: 0.515 AC: 1088 AN: 2112

Alfa AF: 0.427 Hom.: 6905

Bravo AF: 0.548

Asia WGS AF: 0.421 AC: 1466 AN: 3478

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.86
DANN	Benign	0.64
PhyloP100		-0.50
Mutation Taster		=100/0	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: rs2306604; hg19: chr10-60148692; COSMIC: COSV65876392;