rs796052056

Positions:

• chr8-73976397-C-CGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017866.6(TMEM70):​c.117_118dup​(p.Ser40CysfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000974 in 1,436,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: TMEM70 NM_017866.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.36

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-73976397-C-CGT is Pathogenic according to our data. Variant chr8-73976397-C-CGT is described in ClinVar as [Pathogenic]. Clinvar id is 203989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM70	NM_017866.6	c.117_118dup	p.Ser40CysfsTer11	frameshift_variant	1/3	ENST00000312184.6	NP_060336.3
TMEM70	NM_001040613.3	c.117_118dup	p.Ser40CysfsTer11	frameshift_variant	1/3		NP_001035703.1
TMEM70	NR_033334.2	n.204_205dup		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6	c.117_118dup	p.Ser40CysfsTer11	frameshift_variant	1/3	1	NM_017866.6	ENSP00000312599	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000481 AC: 1 AN: 207742 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 114818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000974 AC: 14 AN: 1436894 Hom.: 0 Cov.: 33 AF XY: 0.00000840 AC XY: 6 AN XY: 714450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency nuclear type 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2023	Variant summary: TMEM70 c.117_118dupGT (p.Ser40CysfsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with ATP synthase deficiency in HGMD. The variant allele was found at a frequency of 4.8e-06 in 207742 control chromosomes. c.117_118dupGT has been reported in the literature in individuals affected with Complex V Deficiency, Nuclear Type 2 (Cizkov_2008, Cameron_2011, etc). At least one publication reports reduction in ATP synthase activity in fibroblasts from a patient who was compound heterozygous for the variant and another known loss-of-function variant (Cameron_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Mar 23, 2017	This 15 year old female with severe intellectual disability was found to carry a paternally inherited variant in the TMEM70 gene. She also carries a maternally inherited variant (p.Gly47Glu) in this gene, which is currently classified as a variant of uncertain significance. Previous biochemical analyses do not suggest that this patient has a mitochondrial deficiency. The p.Ser40CysfsX11 variant has been reported previously in the compound heterozygous state in an affected individual. The p.Ser40CysfsX11 variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, a pathogenic variant in MEF2C was identified in this patient. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2023	This sequence change creates a premature translational stop signal (p.Ser40Cysfs*11) in the TMEM70 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM70 are known to be pathogenic (PMID: 18953340, 21147908). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 203989). This premature translational stop signal has been observed in individual(s) with TMEM70-related conditions (PMID: 18953340). This variant is present in population databases (rs765909414, gnomAD 0.003%). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 09, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1_MOD,PM2. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2017

The c.117_118dupGT pathogenic variant in the TMEM70 gene has been reported previously in association with mitochondrial complex V deficiency an individual with psychomotor retardation, hypertrophic cardiomyopathy, lactic acidosis, methylglutaconic aciduria, and isolated deficiency of ATP synthase complex who was heterozygous for the c.117_118dupGT pathogenic variant and another pathogenic variant (Cízková et al., 2008). The c.117_118dupGT variant causes a frameshift starting with codon Serine 40, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Ser40CysfsX11. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.117_118dupGT variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.117_118dupGT as a pathogenic variant. -

Mitochondrial proton-transporting ATP synthase complex deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2018

The p.Ser40CysfsX11 variant in TMEM70 has been previously reported in at least 3 compound heterozygous individuals with ATP synthase deficiency, all of which al so carried the pathogenic c.317-2A>G variant (Cizkova 2008, Cameron 2011, Magner 2015). This variant has also been reported in ClinVar (Variation ID 203989) and has been identified in 3/107484 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org). Functional studies provide some evidence that the p.Ser40CysfsX11 variant may impact protein function, by c ausing a reduction in ATP synthase activity (Cameron 2011). This variant is pred icted to cause a frameshift, which alters the protein?s amino acid sequence begi nning at position 40 and leads to a premature termination codon 11 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Biallelic loss of function of the TMEM70 gene has been associated with AT P synthase deficiency and related features, though this variant may be associate d with a milder phenotype after the neonate period (Honzik 2010, Magner 2015). I n summary, this variant meets criteria to be classified as pathogenic for isolat ed ATP synthase deficiency in an autosomal recessive manner. ACMG/AMP criteria a pplied: PVS1_Strong, PM3_Strong, PM2. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796052056; hg19: chr8-74888632;