8-73981217-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017866.6(TMEM70):c.379A>G(p.Thr127Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,614,150 control chromosomes in the GnomAD database, including 1,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. T127R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 211 hom., cov: 33)

Exomes 𝑓: 0.0076 ( 1047 hom. )

Consequence

TMEM70
NM_017866.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.236

Publications

5 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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
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=0.0019361675).

BP6

Variant 8-73981217-A-G is Benign according to our data. Variant chr8-73981217-A-G is described in ClinVar as Benign. ClinVar VariationId is 137678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017866.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM70	NM_017866.6	MANE Select	c.379A>G	p.Thr127Ala	missense	Exon 3 of 3	NP_060336.3
TMEM70	NM_001040613.3		c.*69A>G		3_prime_UTR	Exon 3 of 3	NP_001035703.1	Q9BUB7-3
TMEM70	NR_033334.2		n.559A>G		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.379A>G	p.Thr127Ala	missense	Exon 3 of 3	ENSP00000312599.5	Q9BUB7-1
TMEM70	ENST00000517439.1	TSL:2	c.*69A>G		3_prime_UTR	Exon 3 of 3	ENSP00000429467.1	Q9BUB7-3
TMEM70	ENST00000416961.6	TSL:2	n.*136A>G		non_coding_transcript_exon	Exon 4 of 4	ENSP00000407695.2	D4PHA6

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2285

AN:

152186

Hom.:

208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0117

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.0324

AC:

8133

AN:

251396

AF XY:

0.0254

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.00760

AC:

11115

AN:

1461846

Hom.:

1047

Cov.:

AF XY:

0.00685

AC XY:

4981

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33480

American (AMR)

AF:

0.201

AC:

8970

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26132

East Asian (EAS)

AF:

0.00809

AC:

321

AN:

39686

South Asian (SAS)

AF:

0.0136

AC:

1173

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000111

AC:

123

AN:

1112004

Other (OTH)

AF:

0.00719

AC:

434

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

609

1218

1827

2436

3045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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:

0.0151

AC:

2298

AN:

152304

Hom.:

211

Cov.:

AF XY:

0.0177

AC XY:

1316

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41566

American (AMR)

AF:

0.132

AC:

2015

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0116

AC:

AN:

5184

South Asian (SAS)

AF:

0.0149

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

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:

0.00399

Hom.:

Bravo

AF:

0.0242

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0242

AC:

2938

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.1

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.00064

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

PhyloP100

0.24

PrimateAI

Benign

0.28

PROVEAN

Benign

0.12

REVEL

Benign

0.045

Sift

Benign

0.81

Sift4G

Benign

0.87

Polyphen

0.0010

Vest4

0.0030

MPC

0.22

ClinPred

0.00098

GERP RS

1.0

Varity_R

0.014

gMVP

0.38

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over