10-58388932-A-G

Variant names:

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

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.441+113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 974,548 control chromosomes in the GnomAD database, including 106,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23180 hom., cov: 33)
  • Exomes 𝑓: 0.45 (82999 hom.)
• Consequence: TFAM NM_003201.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.504

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 (BayesDel_noAF=-0.9).
• BP6: Variant 10-58388932-A-G is Benign according to our data. Variant chr10-58388932-A-G is described in ClinVar as [Benign]. Clinvar id is 684189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAM	NM_003201.3	c.441+113A>G		intron_variant	Intron 4 of 6	ENST00000487519.6	NP_003192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAM	ENST00000487519.6	c.441+113A>G		intron_variant	Intron 4 of 6	1	NM_003201.3	ENSP00000420588.1
TFAM	ENST00000395377.2	c.384+113A>G		intron_variant	Intron 4 of 5	2		ENSP00000378776.2
TFAM	ENST00000373895.7	c.441+113A>G		intron_variant	Intron 4 of 5	2		ENSP00000363002.3
TFAM	ENST00000373899.3	n.711+113A>G		intron_variant	Intron 5 of 7	2

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80253 AN: 151972 Hom.: 23156 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.519

GnomAD4 exome AF: 0.446 AC: 366532 AN: 822460 Hom.: 82999 AF XY: 0.445 AC XY: 188845 AN XY: 424692

Gnomad4 AFR exome AF: 0.789

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.519

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.436

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.528 AC: 80326 AN: 152088 Hom.: 23180 Cov.: 33 AF XY: 0.520 AC XY: 38658 AN XY: 74342

Gnomad4 AFR AF: 0.781

Gnomad4 AMR AF: 0.444

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.515

Alfa AF: 0.419 Hom.: 5859

Bravo AF: 0.548

Asia WGS AF: 0.421 AC: 1466 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.90
CADD	Benign	0.86
DANN	Benign	0.64

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: rs2306604; hg19: chr10-60148692; COSMIC: COSV65876392;