17-30904091-G-C

Variant names:

• chr17-30904091-G-C
• rs1453048171
• NM_024683.4:c.470C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024683.4(TEFM):​c.470C>G​(p.Pro157Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TEFM NM_024683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50
• Publications: 0 publications found

Genes affected

TEFM (HGNC:26223): (transcription elongation factor, mitochondrial) Enables DNA polymerase processivity factor activity. Involved in mitochondrial transcription and oxidative phosphorylation. Located in mitochondrial nucleoid. Part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

TEFM Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 58

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024683.4. 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
	TEFM	NM_024683.4	MANE Select	c.470C>G	p.Pro157Arg	missense	Exon 2 of 4	NP_078959.3	Q96QE5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEFM	ENST00000581216.6	TSL:1 MANE Select	c.470C>G	p.Pro157Arg	missense	Exon 2 of 4	ENSP00000462963.1	Q96QE5-1
	TEFM	ENST00000580840.1	TSL:1	c.470C>G	p.Pro157Arg	missense	Exon 2 of 3	ENSP00000462973.1	J3KTG7
	TEFM	ENST00000876802.1		c.470C>G	p.Pro157Arg	missense	Exon 2 of 3	ENSP00000546861.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Benign	0.92
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.5
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.63		Loss of loop (P = 0.0022)
MVP		0.65
MPC		0.75
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.86

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: rs1453048171; hg19: chr17-29231109;