NM_017866.6:c.580G>A

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

4
14

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

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
TMEM70NM_017866.6 linkc.580G>A p.Val194Met missense_variant Exon 3 of 3 ENST00000312184.6 NP_060336.3 Q9BUB7-1
TMEM70NR_033334.2 linkn.760G>A non_coding_transcript_exon_variant Exon 4 of 4
TMEM70NM_001040613.3 linkc.*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
TMEM70ENST00000312184.6 linkc.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.:
9
Cov.:
33
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.:
33
AF XY:
0.0139
AC XY:
10078
AN XY:
727202
show subpopulations
African (AFR)
AF:
0.00224
AC:
75
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:
1
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
0
1210
2420
3631
4841
6051
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
592
1184
1776
2368
2960
<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
AF:
0.0106
AC:
1613
AN:
152322
Hom.:
9
Cov.:
33
AF XY:
0.0101
AC XY:
753
AN XY:
74492
show subpopulations
African (AFR)
AF:
0.00217
AC:
90
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:
0
AN:
5194
South Asian (SAS)
AF:
0.00601
AC:
29
AN:
4828
European-Finnish (FIN)
AF:
0.0180
AC:
191
AN:
10618
Middle Eastern (MID)
AF:
0.0612
AC:
18
AN:
294
European-Non Finnish (NFE)
AF:
0.0148
AC:
1009
AN:
68028
Other (OTH)
AF:
0.0156
AC:
33
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
83
167
250
334
417
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0139
Hom.:
53
Bravo
AF:
0.00949
TwinsUK
AF:
0.0175
AC:
65
ALSPAC
AF:
0.0148
AC:
57
ESP6500AA
AF:
0.00204
AC:
9
ESP6500EA
AF:
0.0156
AC:
134
ExAC
AF:
0.0122
AC:
1476
Asia WGS
AF:
0.00231
AC:
8
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
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0079
T
Eigen
Benign
-0.013
Eigen_PC
Benign
-0.066
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.81
T
MetaRNN
Benign
0.014
T
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.5
M
PhyloP100
3.0
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.20
Sift
Benign
0.038
D
Sift4G
Uncertain
0.024
D
Polyphen
0.92
P
Vest4
0.065
MPC
0.31
ClinPred
0.032
T
GERP RS
3.6
Varity_R
0.083
gMVP
0.57
Mutation Taster
=95/5
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

Publications

Other links and lift over

dbSNP: rs77410280; hg19: chr8-74893653; COSMIC: COSV56487737; COSMIC: COSV56487737; API