10-58385837-G-C

Variant names:

• chr10-58385837-G-C
• rs4397793
• NM_003201.3:c.101+189G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003201.3(TFAM):​c.101+189G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 151,984 control chromosomes in the GnomAD database, including 19,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.49 (19577 hom., cov: 32)
• Consequence: TFAM NM_003201.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.06
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-58385837-G-C is Benign according to our data. Variant chr10-58385837-G-C is described in ClinVar as Benign. ClinVar VariationId is 684179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAM	NM_003201.3	c.101+189G>C		intron_variant	Intron 1 of 6	ENST00000487519.6	NP_003192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAM	ENST00000487519.6	c.101+189G>C		intron_variant	Intron 1 of 6	1	NM_003201.3	ENSP00000420588.1
TFAM	ENST00000395377.2	c.44+189G>C		intron_variant	Intron 1 of 5	2		ENSP00000378776.2
TFAM	ENST00000373895.7	c.101+189G>C		intron_variant	Intron 1 of 5	2		ENSP00000363002.3
TFAM	ENST00000373899.3	n.304+189G>C		intron_variant	Intron 1 of 7	2

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74351 AN: 151868 Hom.: 19560 Cov.: 32

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.479

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.490 AC: 74417 AN: 151984 Hom.: 19577 Cov.: 32 AF XY: 0.483 AC XY: 35852 AN XY: 74300

African (AFR) AF: 0.701 AC: 29091 AN: 41470

American (AMR) AF: 0.415 AC: 6347 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3468

East Asian (EAS) AF: 0.493 AC: 2535 AN: 5142

South Asian (SAS) AF: 0.380 AC: 1830 AN: 4816

European-Finnish (FIN) AF: 0.337 AC: 3553 AN: 10542

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.409 AC: 27817 AN: 67956

Other (OTH) AF: 0.475 AC: 1003 AN: 2110

Alfa AF: 0.268 Hom.: 568

Bravo AF: 0.507

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.73
PhyloP100		-1.1
PromoterAI		-0.12	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4397793; hg19: chr10-60145597; COSMIC: COSV65876682;