rs3900887

Variant names:

• chr10-58386035-T-A
• rs3900887
• NM_003201.3:c.102-185T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003201.3(TFAM):​c.102-185T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,170 control chromosomes in the GnomAD database, including 1,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.15 (1728 hom., cov: 32)
• Consequence: TFAM NM_003201.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.659
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-58386035-T-A is Benign according to our data. Variant chr10-58386035-T-A is described in ClinVar as Benign. ClinVar VariationId is 1243323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

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.102-185T>A		intron	N/A	NP_003192.1
	TFAM	NM_001270782.2		c.102-185T>A		intron	N/A	NP_001257711.1
	TFAM	NR_073073.2		n.240-185T>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	ENST00000487519.6	TSL:1 MANE Select	c.102-185T>A		intron	N/A	ENSP00000420588.1
	TFAM	ENST00000909231.1		c.102-185T>A		intron	N/A	ENSP00000579290.1
	TFAM	ENST00000935269.1		c.102-203T>A		intron	N/A	ENSP00000605328.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22956 AN: 152052 Hom.: 1730 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.151 AC: 22959 AN: 152170 Hom.: 1728 Cov.: 32 AF XY: 0.148 AC XY: 10979 AN XY: 74404

African (AFR) AF: 0.163 AC: 6771 AN: 41504

American (AMR) AF: 0.119 AC: 1824 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5166

South Asian (SAS) AF: 0.0741 AC: 358 AN: 4830

European-Finnish (FIN) AF: 0.176 AC: 1866 AN: 10606

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11176 AN: 67978

Other (OTH) AF: 0.153 AC: 323 AN: 2112

Alfa AF: 0.153 Hom.: 217

Bravo AF: 0.149

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.3
DANN	Benign	0.85
PhyloP100		-0.66
PromoterAI		0.0081	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: rs3900887; hg19: chr10-60145795;