rs1937

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.35G>C(p.Ser12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,570,732 control chromosomes in the GnomAD database, including 8,794 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 598 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8196 hom. )

Consequence

TFAM
NM_003201.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.569

Publications

71 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 (MetaRNN=0.0016011596).

BP6

Variant 10-58385582-G-C is Benign according to our data. Variant chr10-58385582-G-C is described in ClinVar as Benign. ClinVar VariationId is 670994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 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	HGVSp	Effect	Exon Rank	Protein	UniProt
TFAM	NM_003201.3	MANE Select	c.35G>C	p.Ser12Thr	missense	Exon 1 of 7	NP_003192.1	E5KSU5
TFAM	NM_001270782.2		c.35G>C	p.Ser12Thr	missense	Exon 1 of 6	NP_001257711.1	Q00059-2
TFAM	NR_073073.2		n.173G>C		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFAM	ENST00000487519.6	TSL:1 MANE Select	c.35G>C	p.Ser12Thr	missense	Exon 1 of 7	ENSP00000420588.1	Q00059-1
TFAM	ENST00000909231.1		c.35G>C	p.Ser12Thr	missense	Exon 1 of 7	ENSP00000579290.1
TFAM	ENST00000935269.1		c.35G>C	p.Ser12Thr	missense	Exon 1 of 7	ENSP00000605328.1

Frequencies

GnomAD3 genomes

AF:

0.0781

AC:

11876

AN:

152038

Hom.:

600

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0210

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0745

Gnomad ASJ

AF:

0.0936

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.0714

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.0627

GnomAD2 exomes

AF:

0.0957

AC:

17660

AN:

184556

AF XY:

0.0964

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.0851

Gnomad ASJ exome

AF:

0.0906

Gnomad EAS exome

AF:

0.161

Gnomad FIN exome

AF:

0.0688

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0921

GnomAD4 exome

AF:

0.104

AC:

147916

AN:

1418576

Hom.:

8196

Cov.:

AF XY:

0.104

AC XY:

73293

AN XY:

701584

show subpopulations

African (AFR)

AF:

0.0149

AC:

481

AN:

32356

American (AMR)

AF:

0.0853

AC:

3315

AN:

38868

Ashkenazi Jewish (ASJ)

AF:

0.0939

AC:

2384

AN:

25382

East Asian (EAS)

AF:

0.179

AC:

6643

AN:

37028

South Asian (SAS)

AF:

0.116

AC:

9329

AN:

80478

European-Finnish (FIN)

AF:

0.0666

AC:

3369

AN:

50558

Middle Eastern (MID)

AF:

0.0629

AC:

360

AN:

5720

European-Non Finnish (NFE)

AF:

0.107

AC:

116450

AN:

1089418

Other (OTH)

AF:

0.0950

AC:

5585

AN:

58768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

7368

14736

22105

29473

36841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4296

8592

12888

17184

21480

<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:

0.0780

AC:

11868

AN:

152156

Hom.:

598

Cov.:

AF XY:

0.0788

AC XY:

5862

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0209

AC:

870

AN:

41536

American (AMR)

AF:

0.0741

AC:

1133

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

325

AN:

3472

East Asian (EAS)

AF:

0.167

AC:

859

AN:

5136

South Asian (SAS)

AF:

0.116

AC:

557

AN:

4810

European-Finnish (FIN)

AF:

0.0714

AC:

757

AN:

10606

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7150

AN:

67990

Other (OTH)

AF:

0.0620

AC:

131

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

558

1117

1675

2234

2792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0960

Hom.:

260

Bravo

AF:

0.0749

TwinsUK

AF:

0.116

AC:

430

ALSPAC

AF:

0.105

AC:

404

ESP6500AA

AF:

0.0211

AC:

ESP6500EA

AF:

0.0945

AC:

812

ExAC

AF:

0.0692

AC:

8182

Asia WGS

AF:

0.107

AC:

370

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

TFAM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.12

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.57

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.74

REVEL

Benign

0.025

Sift

Benign

0.27

Sift4G

Uncertain

0.045

Polyphen

0.0080

Vest4

0.034

MPC

0.22

ClinPred

0.0012

GERP RS

0.60

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.45

Mutation Taster

=99/1

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