Genetic Variant TMEM70:p.Arg33Gly (chr8-73976378-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017866.6(TMEM70):c.97C>G(p.Arg33Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,443,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R33R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMEM70
NM_017866.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.487

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045585364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMEM70	NM_017866.6 link	c.97C>G	p.Arg33Gly	missense_variant	Exon 1 of 3	ENST00000312184.6	NP_060336.3
TMEM70	NM_001040613.3 link	c.97C>G	p.Arg33Gly	missense_variant	Exon 1 of 3		NP_001035703.1
TMEM70	NR_033334.2 link	n.184C>G		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6 link	c.97C>G	p.Arg33Gly	missense_variant	Exon 1 of 3	1	NM_017866.6	ENSP00000312599.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000313

AC:

AN:

223984

AF XY:

0.0000243

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000345

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1443984

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718510

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

44158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.0000760

AC:

AN:

39476

South Asian (SAS)

AF:

0.00

AC:

AN:

85442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39866

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110410

Other (OTH)

AF:

0.00

AC:

AN:

59940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000167

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0044

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.43

T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

PhyloP100

-0.49

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.0080

Sift

Benign

0.22

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0020

.;B

Vest4

0.13

MutPred

0.18

Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);

MVP

0.048

MPC

0.32

ClinPred

0.018

GERP RS

-1.6

PromoterAI

0.0035

Neutral

(source)

Varity_R

0.070

gMVP

0.41

Mutation Taster

=98/2

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over