rs61734099

chr8-73981217-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017866.6(TMEM70):c.379A>G(p.Thr127Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,614,150 control chromosomes in the GnomAD database, including 1,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T127R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (211 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (1047 hom.)
• Consequence: TMEM70 NM_017866.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.236

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019361675).
• BP6: Variant 8-73981217-A-G is Benign according to our data. Variant chr8-73981217-A-G is described in ClinVar as [Benign]. Clinvar id is 137678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-73981217-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM70	NM_017866.6	c.379A>G	p.Thr127Ala	missense_variant	3/3	ENST00000312184.6
TMEM70	NM_001040613.3	c.*69A>G		3_prime_UTR_variant	3/3
TMEM70	NR_033334.2	n.559A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM70	ENST00000312184.6	c.379A>G	p.Thr127Ala	missense_variant	3/3	1	NM_017866.6	P1
TMEM70	ENST00000517439.1	c.*69A>G		3_prime_UTR_variant	3/3	2
TMEM70	ENST00000519551.1	n.270A>G		non_coding_transcript_exon_variant	3/3	2
TMEM70	ENST00000416961.6	c.*136A>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2285 AN: 152186 Hom.: 208 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.0324 AC: 8133 AN: 251396 Hom.: 850 AF XY: 0.0254 AC XY: 3447 AN XY: 135874

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0109

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.00760 AC: 11115 AN: 1461846 Hom.: 1047 Cov.: 33 AF XY: 0.00685 AC XY: 4981 AN XY: 727226

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00809

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00719

GnomAD4 genome AF: 0.0151 AC: 2298 AN: 152304 Hom.: 211 Cov.: 33 AF XY: 0.0177 AC XY: 1316 AN XY: 74472

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00213 Hom.: 19

Bravo AF: 0.0242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0242 AC: 2938

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency nuclear type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2014

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. -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.1
Dann	Benign	0.56
DEOGEN2	Benign	0.00064	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.045
Sift	Benign	0.81	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.0030
MPC		0.22
ClinPred		0.00098	T
GERP RS		1.0
Varity_R		0.014
gMVP		0.38

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

Other links and lift over

dbSNP: rs61734099; hg19: chr8-74893452; COSMIC: COSV56487786; COSMIC: COSV56487786;