10-58388932-A-T

Variant names:

• chr10-58388932-A-T
• rs2306604
• NM_003201.3:c.441+113A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003201.3(TFAM):​c.441+113A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TFAM NM_003201.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• Publications: 42 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	NM_003201.3	MANE Select	c.441+113A>T		intron	N/A	NP_003192.1
	TFAM	NM_001270782.2		c.441+113A>T		intron	N/A	NP_001257711.1
	TFAM	NR_073073.2		n.646+113A>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	ENST00000487519.6	TSL:1 MANE Select	c.441+113A>T		intron	N/A	ENSP00000420588.1
	TFAM	ENST00000395377.2	TSL:2	c.384+113A>T		intron	N/A	ENSP00000378776.2
	TFAM	ENST00000373895.7	TSL:2	c.441+113A>T		intron	N/A	ENSP00000363002.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 824836 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 425866

African (AFR) AF: 0.00 AC: 0 AN: 19676

American (AMR) AF: 0.00 AC: 0 AN: 27318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18752

East Asian (EAS) AF: 0.00 AC: 0 AN: 33538

South Asian (SAS) AF: 0.00 AC: 0 AN: 61074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2776

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 593820

Other (OTH) AF: 0.00 AC: 0 AN: 38028

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 6905

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.72
DANN	Benign	0.61
PhyloP100		-0.50

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: rs2306604; hg19: chr10-60148692;