chr8-73976397-C-CGT

Variant names:

• chr8-73976397-C-CGT
• rs796052056
• NM_017866.6:c.117_118dupGT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_017866.6(TMEM70):​c.117_118dupGT​(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 (★★). ClinVar reports functional evidence for this variant: "SCV003801135: 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)." and additional evidence is available in ClinVar. 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003801135: 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).; SCV000966910: Functional studies provide some evidence that the p.Ser40CysfsX11 variant may impact protein function, by causing a reduction in ATP synthase activity (Cameron 2011).
• 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 VariationId is 203989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017866.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	NM_017866.6	MANE Select	c.117_118dupGT	p.Ser40CysfsTer11	frameshift	Exon 1 of 3	NP_060336.3
	TMEM70	NM_001040613.3		c.117_118dupGT	p.Ser40CysfsTer11	frameshift	Exon 1 of 3	NP_001035703.1	Q9BUB7-3
	TMEM70	NR_033334.2		n.204_205dupGT		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.117_118dupGT	p.Ser40CysfsTer11	frameshift	Exon 1 of 3	ENSP00000312599.5	Q9BUB7-1
	TMEM70	ENST00000517439.1	TSL:2	c.117_118dupGT	p.Ser40CysfsTer11	frameshift	Exon 1 of 3	ENSP00000429467.1	Q9BUB7-3
	TMEM70	ENST00000416961.6	TSL:2	n.117_118dupGT		non_coding_transcript_exon	Exon 1 of 4	ENSP00000407695.2	D4PHA6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000481 AC: 1 AN: 207742 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 42880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.00 AC: 0 AN: 84498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4998

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1107314

Other (OTH) AF: 0.00 AC: 0 AN: 59640

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (5)
1	-	-	Mitochondrial proton-transporting ATP synthase complex deficiency (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs796052056; hg19: chr8-74888632;