Genetic Variant TEFM:p.Met256Ile (chr17-30899484-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024683.4(TEFM):c.768G>A(p.Met256Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,824 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: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TEFM
NM_024683.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20

Publications

0 publications found

Variant links:

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

TEFM links:

ENSG00000275185 (HGNC:):

ENSG00000275185 links:

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ACMG classification

Classification was made for transcript

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, 0.889

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.768G>A	p.Met256Ile	missense	Exon 4 of 4	NP_078959.3	Q96QE5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TEFM	ENST00000581216.6	TSL:1 MANE Select	c.768G>A	p.Met256Ile	missense	Exon 4 of 4	ENSP00000462963.1	Q96QE5-1
TEFM	ENST00000580840.1	TSL:1	c.*893G>A		3_prime_UTR	Exon 3 of 3	ENSP00000462973.1	J3KTG7
TEFM	ENST00000876802.1		c.618G>A	p.Met206Ile	missense	Exon 3 of 3	ENSP00000546861.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249312

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.024

MutationAssessor

Uncertain

2.5

PhyloP100

5.2

PrimateAI

Uncertain

0.48

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.74

Gain of catalytic residue at L261 (P = 0.1308)

MVP

0.58

MPC

0.76

ClinPred

0.88

GERP RS

6.1

Varity_R

0.88

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over