rs199815125

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017866.6(TMEM70):c.128G>A(p.Ser43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000909 in 1,583,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S43S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

TMEM70
NM_017866.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.494

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07188466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM70	NM_017866.6 linkuse as main transcript	c.128G>A	p.Ser43Asn	missense_variant	1/3	ENST00000312184.6
TMEM70	NM_001040613.3 linkuse as main transcript	c.128G>A	p.Ser43Asn	missense_variant	1/3
TMEM70	NR_033334.2 linkuse as main transcript	n.215G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM70	ENST00000312184.6 linkuse as main transcript	c.128G>A	p.Ser43Asn	missense_variant	1/3	1	NM_017866.6	P1	Q9BUB7-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000856

AC:

AN:

198590

Hom.:

AF XY:

0.0000727

AC XY:

AN XY:

110006

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000295

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.0000887

AC:

127

AN:

1431352

Hom.:

Cov.:

AF XY:

0.0000956

AC XY:

AN XY:

711056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000780

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000229

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.000112

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000475

AC:

ExAC

AF:

0.0000677

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency nuclear type 2

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 12, 2022	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 43 of the TMEM70 protein (p.Ser43Asn). This variant is present in population databases (rs199815125, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TMEM70-related conditions. ClinVar contains an entry for this variant (Variation ID: 363689). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 03, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2021

The c.128G>A (p.S43N) alteration is located in exon 1 (coding exon 1) of the TMEM70 gene. This alteration results from a G to A substitution at nucleotide position 128, causing the serine (S) at amino acid position 43 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.69

Cadd

Benign

9.7

Dann

Benign

0.76

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.072

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.031

Sift

Benign

0.074

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.18

.;B

Vest4

0.097

MVP

0.17

MPC

0.21

ClinPred

0.067

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over