chr8-73981153-A-G

Variant names:

• chr8-73981153-A-G
• rs183973249
• NM_017866.6:c.317-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Strong PS3 PP5_Very_Strong

The NM_017866.6(TMEM70):​c.317-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,608,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915260: Functional studies using fibroblasts from probands harboring the c.317-2A>G variant showed a significant deficiency in ATP synthase compared with control cells, and ultrastructural analysis revealed defects in mitochondrial morphology (Havlíďková Karbanová et al. 2012" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TMEM70 NM_017866.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 8.61
• Publications: 29 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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 2.0804598 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915260: Functional studies using fibroblasts from probands harboring the c.317-2A>G variant showed a significant deficiency in ATP synthase compared with control cells, and ultrastructural analysis revealed defects in mitochondrial morphology (Havlíďková Karbanová et al. 2012; Braczynski et al. 2015).; SCV001374009: Studies have shown that disruption of this splice site alters TMEM70 gene expression (PMID: 1895334).; SCV003801136: Several publications report experimental evidence evaluating an impact on protein function, showing the variant results in a strong reduction in ATP synthesis activity (ranging from 40% to 95% reduction in activity depending on patient and type of tissue) (Cizkova_2008, Cameron_2011, Torraco_2012, Havlickova-Karbanova_2012, Braczynski_2015) as well as a complete absense of TMEM70 protein (Hejzlarova_2011, Torraco_2012) or mRNA (Torraco_2012) in patient fibroblasts.; SCV000329823: cDNA analysis found that c.317-2A>G leads to abnormal splicing and loss of normal TMEM70 transcript (PMID: 18953340); SCV002817231: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 22433607, 20937241, and 18953340).; SCV004113915: Functional studies showed this variant leads to absence of the TMEM70 protein and reduction in functional ATP synthase to less than 30% of control values (Havlíčková Karbanová et al. 2012. PubMed ID: 22433607).
• PP5: Variant 8-73981153-A-G is Pathogenic according to our data. Variant chr8-73981153-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 540.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.317-2A>G		splice_acceptor intron	N/A	NP_060336.3
	TMEM70	NM_001040613.3		c.*7-2A>G		splice_acceptor intron	N/A	NP_001035703.1	Q9BUB7-3
	TMEM70	NR_033334.2		n.497-2A>G		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.317-2A>G		splice_acceptor intron	N/A	ENSP00000312599.5	Q9BUB7-1
	TMEM70	ENST00000517439.1	TSL:2	c.*7-2A>G		splice_acceptor intron	N/A	ENSP00000429467.1	Q9BUB7-3
	TMEM70	ENST00000416961.6	TSL:2	n.*74-2A>G		splice_acceptor intron	N/A	ENSP00000407695.2	D4PHA6

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000718 AC: 18 AN: 250692 AF XY: 0.0000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1456538 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 725022

African (AFR) AF: 0.0000300 AC: 1 AN: 33362

American (AMR) AF: 0.000247 AC: 11 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.000122 AC: 135 AN: 1107730

Other (OTH) AF: 0.0000831 AC: 5 AN: 60162

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74438

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (14)
6	-	-	not provided (6)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	See cases (1)
1	-	-	TMEM70-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.6
GERP RS		5.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs183973249; hg19: chr8-74893388; COSMIC: COSV56488440; COSMIC: COSV56488440;