rs61732273

Positions:

• chr8-73981184-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000312184.6(TMEM70):​c.346C>G​(p.Leu116Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,674 control chromosomes in the GnomAD database, including 463 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (38 hom., cov: 33)
  • Exomes 𝑓: 0.020 (425 hom.)
• Consequence: TMEM70 ENST00000312184.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0300

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=0.0027802587).
• BP6: Variant 8-73981184-C-G is Benign according to our data. Variant chr8-73981184-C-G is described in ClinVar as [Benign]. Clinvar id is 130599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-73981184-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.021 (3200/152246) while in subpopulation SAS AF= 0.035 (169/4826). AF 95% confidence interval is 0.0307. There are 38 homozygotes in gnomad4. There are 1678 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM70	NM_017866.6	c.346C>G	p.Leu116Val	missense_variant	3/3	ENST00000312184.6	NP_060336.3
TMEM70	NM_001040613.3	c.*36C>G		3_prime_UTR_variant	3/3		NP_001035703.1
TMEM70	NR_033334.2	n.526C>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6	c.346C>G	p.Leu116Val	missense_variant	3/3	1	NM_017866.6	ENSP00000312599	P1
TMEM70	ENST00000517439.1	c.*36C>G		3_prime_UTR_variant	3/3	2		ENSP00000429467
TMEM70	ENST00000519551.1	n.237C>G		non_coding_transcript_exon_variant	3/3	2
TMEM70	ENST00000416961.6	c.*103C>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	2		ENSP00000407695

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3189 AN: 152128 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0474

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.0235 AC: 5905 AN: 251328 Hom.: 91 AF XY: 0.0243 AC XY: 3296 AN XY: 135856

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.0173

Gnomad SAS exome AF: 0.0369

Gnomad FIN exome AF: 0.0457

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0202 AC: 29544 AN: 1461428 Hom.: 425 Cov.: 33 AF XY: 0.0209 AC XY: 15179 AN XY: 727028

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.0244

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.0366

Gnomad4 FIN exome AF: 0.0436

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0210 AC: 3200 AN: 152246 Hom.: 38 Cov.: 33 AF XY: 0.0225 AC XY: 1678 AN XY: 74452

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0474

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0193 Hom.: 30

Bravo AF: 0.0179

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0235 AC: 2850

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0209

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TMEM70: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2012	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.022
DANN	Benign	0.50
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.83	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.056
Sift	Benign	1.0	T
Sift4G	Benign	0.96	T
Polyphen		0.035	B
Vest4		0.011
MPC		0.24
ClinPred		0.0027	T
GERP RS		-9.7
Varity_R		0.019
gMVP		0.43

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: rs61732273; hg19: chr8-74893419;