dbSNP rs12247015: TFAM:c.-229A>G (chr10-58385319-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

TFAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFAM	NM_003201.3	MANE Select	c.-229A>G	upstream_gene	N/A	NP_003192.1	E5KSU5
TFAM	NM_001270782.2		c.-229A>G	upstream_gene	N/A	NP_001257711.1	Q00059-2
TFAM	NR_073073.2		n.-91A>G	upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TFAM	ENST00000487519.6	TSL:1 MANE Select	c.-229A>G	upstream_gene	N/A	ENSP00000420588.1	Q00059-1
TFAM	ENST00000909231.1		c.-229A>G	upstream_gene	N/A	ENSP00000579290.1
TFAM	ENST00000935269.1		c.-229A>G	upstream_gene	N/A	ENSP00000605328.1

Frequencies

GnomAD3 genomes

AF:

0.493

AC:

75019

AN:

152022

Hom.:

20792

Cov.:

show subpopulations

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.:

AF XY:

0.393

AC XY:

94647

AN XY:

240946

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

5231

10462

15692

20923

26154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

566

1132

1698

2264

2830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.494

AC:

75083

AN:

152140

Hom.:

20812

Cov.:

AF XY:

0.482

AC XY:

35840

AN XY:

74364

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1826

3652

5477

7303

9129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.357

Hom.:

1368

Bravo

AF:

0.511

Asia WGS

AF:

0.237

AC:

826

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.1

(source)

DANN

Benign

0.62

PhyloP100

-1.0

PromoterAI

-0.089

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over