rs1937

chr10-58385582-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.569

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]

ACMG classification

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	UniProt
TFAM	NM_003201.3	c.35G>C	p.Ser12Thr	missense_variant	1/7	ENST00000487519.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFAM	ENST00000487519.6	c.35G>C	p.Ser12Thr	missense_variant	1/7	1	NM_003201.3	P1
TFAM	ENST00000373895.7	c.35G>C	p.Ser12Thr	missense_variant	1/6	2
TFAM	ENST00000373899.3	n.238G>C		non_coding_transcript_exon_variant	1/8	2
TFAM	ENST00000395377.2			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0781 AC: 11876 AN: 152038 Hom.: 600 Cov.: 32

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

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.: 32 AF XY: 0.104 AC XY: 73293 AN XY: 701584

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.: 32 AF XY: 0.0788 AC XY: 5862 AN XY: 74392

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: 93

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

TFAM-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	17
Dann	Benign	0.68
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs1937; hg19: chr10-60145342; COSMIC: COSV65876244; COSMIC: COSV65876244;