dbSNP rs61732273: TMEM70:p.Leu116Val (chr8-73981184-C-G) – ACMG Classification: Benign (-20 pts)

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.346C>G(p.Leu116Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,674 control chromosomes in the GnomAD database, including 463 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 (★★).

Frequency

Genomes: 𝑓 0.021 ( 38 hom., cov: 33)

Exomes 𝑓: 0.020 ( 425 hom. )

Consequence

TMEM70
NM_017866.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0300

Publications

12 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=0.0027802587).

BP6

Variant 8-73981184-C-G is Benign according to our data. Variant chr8-73981184-C-G is described in ClinVar as Benign. ClinVar VariationId is 130599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.021 (3200/152246) while in subpopulation SAS AF = 0.035 (169/4826). AF 95% confidence interval is 0.0307. There are 38 homozygotes in GnomAd4. There are 1678 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

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.346C>G	p.Leu116Val	missense	Exon 3 of 3	NP_060336.3
TMEM70	NM_001040613.3		c.*36C>G		3_prime_UTR	Exon 3 of 3	NP_001035703.1	Q9BUB7-3
TMEM70	NR_033334.2		n.526C>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.346C>G	p.Leu116Val	missense	Exon 3 of 3	ENSP00000312599.5	Q9BUB7-1
TMEM70	ENST00000517439.1	TSL:2	c.*36C>G		3_prime_UTR	Exon 3 of 3	ENSP00000429467.1	Q9BUB7-3
TMEM70	ENST00000416961.6	TSL:2	n.*103C>G		non_coding_transcript_exon	Exon 4 of 4	ENSP00000407695.2	D4PHA6

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3189

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.0152

Gnomad SAS

AF:

0.0350

Gnomad FIN

AF:

0.0474

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.0235

AC:

5905

AN:

251328

AF XY:

0.0243

show subpopulations

Gnomad AFR exome

AF:

0.0180

Gnomad AMR exome

AF:

0.0167

Gnomad ASJ exome

AF:

0.0251

Gnomad EAS exome

AF:

0.0173

Gnomad FIN exome

AF:

0.0457

Gnomad NFE exome

AF:

0.0191

Gnomad OTH exome

AF:

0.0289

GnomAD4 exome

AF:

0.0202

AC:

29544

AN:

1461428

Hom.:

425

Cov.:

AF XY:

0.0209

AC XY:

15179

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.0173

AC:

580

AN:

33476

American (AMR)

AF:

0.0171

AC:

763

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

637

AN:

26130

East Asian (EAS)

AF:

0.0156

AC:

618

AN:

39688

South Asian (SAS)

AF:

0.0366

AC:

3155

AN:

86232

European-Finnish (FIN)

AF:

0.0436

AC:

2327

AN:

53352

Middle Eastern (MID)

AF:

0.0297

AC:

171

AN:

5766

European-Non Finnish (NFE)

AF:

0.0180

AC:

20058

AN:

1111682

Other (OTH)

AF:

0.0205

AC:

1235

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

1422

2844

4265

5687

7109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

776

1552

2328

3104

3880

<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:

0.0210

AC:

3200

AN:

152246

Hom.:

Cov.:

AF XY:

0.0225

AC XY:

1678

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0184

AC:

766

AN:

41528

American (AMR)

AF:

0.0147

AC:

224

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3466

East Asian (EAS)

AF:

0.0152

AC:

AN:

5188

South Asian (SAS)

AF:

0.0350

AC:

169

AN:

4826

European-Finnish (FIN)

AF:

0.0474

AC:

503

AN:

10606

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0195

AC:

1325

AN:

68024

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

159

318

478

637

796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0193

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.0172

AC:

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0235

AC:

2850

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.0176

EpiControl

AF:

0.0209

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.022

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0020

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.83

PhyloP100

-0.030

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.66

REVEL

Benign

0.056

Sift

Benign

1.0

Sift4G

Benign

0.96

Polyphen

0.035

Vest4

0.011

MPC

0.24

ClinPred

0.0027

GERP RS

-9.7

Varity_R

0.019

gMVP

0.43

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