8-73978750-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_017866.6(TMEM70):c.211-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,134 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 18 hom. )

Consequence

TMEM70
NM_017866.6 splice_region, intron

Scores

Splicing: ADA: 0.00001989

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -0.181

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 8-73978750-C-T is Benign according to our data. Variant chr8-73978750-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137677.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0023 (349/151860) while in subpopulation NFE AF = 0.00396 (269/67936). AF 95% confidence interval is 0.00357. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TMEM70	NM_017866.6 link	c.211-6C>T	splice_region_variant, intron_variant	Intron 1 of 2	ENST00000312184.6	NP_060336.3	Q9BUB7-1
TMEM70	NM_001040613.3 link	c.211-6C>T	splice_region_variant, intron_variant	Intron 1 of 2		NP_001035703.1	Q9BUB7-3
TMEM70	NR_033334.2 link	n.298-6C>T	splice_region_variant, intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6 link	c.211-6C>T		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_017866.6	ENSP00000312599.5		Q9BUB7-1

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

351

AN:

151744

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000944

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.000666

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00396

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00241

AC:

605

AN:

251414

AF XY:

0.00248

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00406

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00351

AC:

5124

AN:

1461274

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

2479

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33462

American (AMR)

AF:

0.00114

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00150

AC:

129

AN:

86244

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00413

AC:

4586

AN:

1111520

Other (OTH)

AF:

0.00336

AC:

203

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

250

500

750

1000

1250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00230

AC:

349

AN:

151860

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

151

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.000942

AC:

AN:

41422

American (AMR)

AF:

0.00111

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00125

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000666

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00396

AC:

269

AN:

67936

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00309

Hom.:

Bravo

AF:

0.00245

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMEM70: BS2 -

Sep 13, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:3

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive disease

Uncertain:1

Aug 06, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 18, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.0

(source)

DANN

Benign

0.79

PhyloP100

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: 25

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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