rs1937

Positions:

chr10-58385582-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

TFAM (HGNC:):

TFAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFAM	NM_003201.3 linkuse as main transcript	c.35G>C	p.Ser12Thr	missense_variant	1/7	ENST00000487519.6	NP_003192.1	Q00059-1E5KSU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TFAM	ENST00000487519.6 linkuse as main transcript	c.35G>C	p.Ser12Thr	missense_variant	1/7	1	NM_003201.3	ENSP00000420588.1	Q00059-1
TFAM	ENST00000373895.7 linkuse as main transcript	c.35G>C	p.Ser12Thr	missense_variant	1/6	2		ENSP00000363002.3	Q00059-2
TFAM	ENST00000373899.3 linkuse as main transcript	n.238G>C		non_coding_transcript_exon_variant	1/8	2
TFAM	ENST00000395377.2 linkuse as main transcript	c.-23G>C		upstream_gene_variant		2		ENSP00000378776.2	H7BYN3

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

GnomAD3 exomes

AF:

0.0957

AC:

17660

AN:

184556

Hom.:

995

AF XY:

0.0964

AC XY:

9467

AN XY:

98242

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 SAS exome

AF:

0.114

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

Gnomad4 AFR exome

AF:

0.0149

Gnomad4 AMR exome

AF:

0.0853

Gnomad4 ASJ exome

AF:

0.0939

Gnomad4 EAS exome

AF:

0.179

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.0666

Gnomad4 NFE exome

AF:

0.107

Gnomad4 OTH exome

AF:

0.0950

GnomAD4 genome

AF:

0.0780

AC:

11868

AN:

152156

Hom.:

598

Cov.:

AF XY:

0.0788

AC XY:

5862

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0209

Gnomad4 AMR

AF:

0.0741

Gnomad4 ASJ

AF:

0.0936

Gnomad4 EAS

AF:

0.167

Gnomad4 SAS

AF:

0.116

Gnomad4 FIN

AF:

0.0714

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.0620

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

TFAM-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.36

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.025

Sift

Benign

0.27

T;T

Sift4G

Uncertain

0.045

D;T

Polyphen

0.0080

B;.

Vest4

0.034

MPC

0.22

ClinPred

0.0012

GERP RS

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over