rs77410280

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017866.6(TMEM70):c.580G>A(p.Val194Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,614,142 control chromosomes in the GnomAD database, including 189 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 9 hom., cov: 33)

Exomes 𝑓: 0.014 ( 180 hom. )

Consequence

TMEM70
NM_017866.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.97

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:

TMEM70 (HGNC:):

TMEM70 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013616115).

BP6

Variant 8-73981418-G-A is Benign according to our data. Variant chr8-73981418-G-A is described in ClinVar as [Benign]. Clinvar id is 218747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-73981418-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0106 (1613/152322) while in subpopulation NFE AF= 0.0148 (1009/68028). AF 95% confidence interval is 0.0141. There are 9 homozygotes in gnomad4. There are 753 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM70	NM_017866.6 linkuse as main transcript	c.580G>A	p.Val194Met	missense_variant	3/3	ENST00000312184.6	NP_060336.3	Q9BUB7-1
TMEM70	NM_001040613.3 linkuse as main transcript	c.*270G>A		3_prime_UTR_variant	3/3		NP_001035703.1	Q9BUB7-3
TMEM70	NR_033334.2 linkuse as main transcript	n.760G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM70	ENST00000312184.6 linkuse as main transcript	c.580G>A	p.Val194Met	missense_variant	3/3	1	NM_017866.6	ENSP00000312599.5	Q9BUB7-1
TMEM70	ENST00000416961.6 linkuse as main transcript	n.*337G>A		non_coding_transcript_exon_variant	4/4	2		ENSP00000407695.2	D4PHA6
TMEM70	ENST00000519551.1 linkuse as main transcript	n.471G>A		non_coding_transcript_exon_variant	3/3	2
TMEM70	ENST00000416961.6 linkuse as main transcript	n.*337G>A		3_prime_UTR_variant	4/4	2		ENSP00000407695.2	D4PHA6

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1612

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0125

AC:

3141

AN:

251422

Hom.:

AF XY:

0.0126

AC XY:

1707

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00636

Gnomad ASJ exome

AF:

0.0375

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00686

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0139

AC:

20381

AN:

1461820

Hom.:

180

Cov.:

AF XY:

0.0139

AC XY:

10078

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.00702

Gnomad4 ASJ exome

AF:

0.0347

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00723

Gnomad4 FIN exome

AF:

0.0177

Gnomad4 NFE exome

AF:

0.0147

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0106

AC:

1613

AN:

152322

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

753

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.00856

Gnomad4 ASJ

AF:

0.0323

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.0180

Gnomad4 NFE

AF:

0.0148

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.00949

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0156

AC:

134

ExAC

AF:

0.0122

AC:

1476

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0175

EpiControl

AF:

0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex V (ATP synthase) deficiency nuclear type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Mar 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0079

Eigen

Benign

-0.013

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.038

Sift4G

Uncertain

0.024

Polyphen

0.92

Vest4

0.065

MPC

0.31

ClinPred

0.032

GERP RS

3.6

Varity_R

0.083

gMVP

0.57

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