NM_017866.6:c.580G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017866.6(TMEM70):c.580G>A(p.Val194Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,614,142 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V194L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 9 hom., cov: 33)

Exomes 𝑓: 0.014 ( 180 hom. )

Consequence

TMEM70
NM_017866.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.97

Publications

10 publications found

Variant links:

Genes affected

TMEM70 (HGNC:26050): (transmembrane protein 70) This gene likely encodes a mitochondrial membrane protein. The encoded protein may play a role in biogenesis of mitochondrial ATP synthase. Mutations in this gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to ATP synthase deficiency. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

TMEM70 Gene-Disease associations (from GenCC):

mitochondrial complex V (ATP synthase) deficiency, nuclear type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

TMEM70 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013616115).

BP6

Variant 8-73981418-G-A is Benign according to our data. Variant chr8-73981418-G-A is described in ClinVar as [Benign]. Clinvar id is 218747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1613/152322) while in subpopulation NFE AF = 0.0148 (1009/68028). AF 95% confidence interval is 0.0141. There are 9 homozygotes in GnomAd4. There are 753 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM70	NM_017866.6 link	c.580G>A	p.Val194Met	missense_variant	Exon 3 of 3	ENST00000312184.6	NP_060336.3	Q9BUB7-1
TMEM70	NR_033334.2 link	n.760G>A		non_coding_transcript_exon_variant	Exon 4 of 4
TMEM70	NM_001040613.3 link	c.*270G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001035703.1	Q9BUB7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6 link	c.580G>A	p.Val194Met	missense_variant	Exon 3 of 3	1	NM_017866.6	ENSP00000312599.5		Q9BUB7-1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1612

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0125

AC:

3141

AN:

251422

AF XY:

0.0126

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00636

Gnomad ASJ exome

AF:

0.0375

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0139

AC:

20381

AN:

1461820

Hom.:

180

Cov.:

AF XY:

0.0139

AC XY:

10078

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

33480

American (AMR)

AF:

0.00702

AC:

314

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0347

AC:

906

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00723

AC:

624

AN:

86258

European-Finnish (FIN)

AF:

0.0177

AC:

944

AN:

53402

Middle Eastern (MID)

AF:

0.0303

AC:

175

AN:

5768

European-Non Finnish (NFE)

AF:

0.0147

AC:

16362

AN:

1111976

Other (OTH)

AF:

0.0162

AC:

980

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1210

2420

3631

4841

6051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0106

AC:

1613

AN:

152322

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

753

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41568

American (AMR)

AF:

0.00856

AC:

131

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00601

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10618

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1009

AN:

68028

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

167

250

334

417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0139

Hom.:

Bravo

AF:

0.00949

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0156

AC:

134

ExAC

AF:

0.0122

AC:

1476

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0175

EpiControl

AF:

0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 06, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0079

Eigen

Benign

-0.013

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.5

PhyloP100

3.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.038

Sift4G

Uncertain

0.024

Polyphen

0.92

Vest4

0.065

MPC

0.31

ClinPred

0.032

GERP RS

3.6

Varity_R

0.083

gMVP

0.57

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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NM_017866.6:c.580G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over