10-58385557-C-G

Position:

chr10-58385557-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003201.3(TFAM):c.10C>G(p.Leu4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,565,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TFAM
NM_003201.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.113

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10116023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFAM	NM_003201.3 linkuse as main transcript	c.10C>G	p.Leu4Val	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.10C>G	p.Leu4Val	missense_variant	1/7	1	NM_003201.3	ENSP00000420588.1	Q00059-1
TFAM	ENST00000373895.7 linkuse as main transcript	c.10C>G	p.Leu4Val	missense_variant	1/6	2		ENSP00000363002.3	Q00059-2
TFAM	ENST00000373899.3 linkuse as main transcript	n.213C>G		non_coding_transcript_exon_variant	1/8	2
TFAM	ENST00000395377.2 linkuse as main transcript	c.-48C>G		upstream_gene_variant		2		ENSP00000378776.2	H7BYN3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000354

AC:

AN:

1413618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698630

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000789

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000341

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000110

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.10C>G (p.L4V) alteration is located in exon 1 (coding exon 1) of the TFAM gene. This alteration results from a C to G substitution at nucleotide position 10, causing the leucine (L) at amino acid position 4 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the TFAM protein (p.Leu4Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TFAM-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.066

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.097

B;.

Vest4

0.11

MutPred

0.22

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.10

MPC

0.25

ClinPred

0.12

GERP RS

-0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.066

gMVP

0.55

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