10-58385582-G-A

Variant names:

• chr10-58385582-G-A
• rs1937
• NM_003201.3:c.35G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003201.3(TFAM):​c.35G>A​(p.Ser12Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S12T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TFAM NM_003201.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.569
• Publications: 0 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: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07547602).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	NM_003201.3	MANE Select	c.35G>A	p.Ser12Asn	missense	Exon 1 of 7	NP_003192.1	E5KSU5
	TFAM	NM_001270782.2		c.35G>A	p.Ser12Asn	missense	Exon 1 of 6	NP_001257711.1	Q00059-2
	TFAM	NR_073073.2		n.173G>A		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAM	ENST00000487519.6	TSL:1 MANE Select	c.35G>A	p.Ser12Asn	missense	Exon 1 of 7	ENSP00000420588.1	Q00059-1
	TFAM	ENST00000909231.1		c.35G>A	p.Ser12Asn	missense	Exon 1 of 7	ENSP00000579290.1
	TFAM	ENST00000935269.1		c.35G>A	p.Ser12Asn	missense	Exon 1 of 7	ENSP00000605328.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418764 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 701670

African (AFR) AF: 0.0000309 AC: 1 AN: 32356

American (AMR) AF: 0.00 AC: 0 AN: 38874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37050

South Asian (SAS) AF: 0.00 AC: 0 AN: 80486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089560

Other (OTH) AF: 0.00 AC: 0 AN: 58770

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.57
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.039
Sift	Benign	0.16	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.051
MutPred		0.26		Loss of loop (P = 0.0374)
MVP		0.16
MPC		0.22
ClinPred		0.29	T
GERP RS		0.60
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.42
Mutation Taster		=98/2	polymorphism

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: rs1937; hg19: chr10-60145342;