Genetic Variant TFAM:c.-229A>T (chr10-58385319-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003201.3(TFAM):c.-229A>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 606,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000066 ( 0 hom. )

Consequence

TFAM
NM_003201.3 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.03

Publications

22 publications found

Variant links:

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)

TFAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAM	NM_003201.3 link	c.-229A>T		upstream_gene_variant		ENST00000487519.6	NP_003192.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
TFAM	ENST00000487519.6 link	c.-229A>T	upstream_gene_variant	1	NM_003201.3	ENSP00000420588.1
TFAM	ENST00000373895.7 link	c.-229A>T	upstream_gene_variant	2		ENSP00000363002.3
TFAM	ENST00000373899.3 link	n.-26A>T	upstream_gene_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000661

AC:

AN:

454008

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

241298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13010

American (AMR)

AF:

0.00

AC:

AN:

24410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14280

East Asian (EAS)

AF:

0.00

AC:

AN:

29886

South Asian (SAS)

AF:

0.00

AC:

AN:

50130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1994

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

266690

Other (OTH)

AF:

0.00

AC:

AN:

25798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

1368

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.7

(source)

DANN

Benign

0.70

PhyloP100

-1.0

PromoterAI

0.044

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over