rs183973249

Positions:

• chr8-73981153-A-G
• chr8-73981153-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017866.6(TMEM70):​c.317-2A>G variant causes a splice acceptor 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TMEM70 NM_017866.6 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 8.61

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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 2.0791826 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-73981153-A-G is Pathogenic according to our data. Variant chr8-73981153-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-73981153-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM70	NM_017866.6	c.317-2A>G		splice_acceptor_variant		ENST00000312184.6	NP_060336.3
TMEM70	NM_001040613.3	c.*7-2A>G		splice_acceptor_variant			NP_001035703.1
TMEM70	NR_033334.2	n.497-2A>G		splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6	c.317-2A>G		splice_acceptor_variant		1	NM_017866.6	ENSP00000312599	P1
TMEM70	ENST00000517439.1	c.*7-2A>G		splice_acceptor_variant		2		ENSP00000429467
TMEM70	ENST00000416961.6	c.*74-2A>G		splice_acceptor_variant, NMD_transcript_variant		2		ENSP00000407695
TMEM70	ENST00000519551.1	n.208-2A>G		splice_acceptor_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0000718 AC: 18 AN: 250692 Hom.: 0 AF XY: 0.0000885 AC XY: 12 AN XY: 135588

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 SAS 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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000247

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: 0.000122

Gnomad4 OTH exome AF: 0.0000831

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency nuclear type 2 Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 22, 2018	The TMEM70 c.317-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product.Across a selection of available literature, the c.317-2A>G variant has been reported in a homozygous state in 36 probands with mitochondrial complex V (ATP Synthase) deficiency, nuclear type (Cizkova et al. 2008; Tort et al. 2011; Braczynski et al. 2015). Cizkova et al. (2008) further demonstrated segregation of the c.317-2A>G variant in six families, in which all the affected individuals were homozygous, all parents were heterozygous, and unaffected siblings were either wild type or heterozygous for the variant. The c.317-2A>G variant was absent from 101 controls and is reported at a frequency of 0.00035 in the Latino population of the Exome Aggregation Consortium. The c.317-2A>G variant occurs at a canonical splice site and has been shown to result in aberrant splicing and loss of the transcript (Cizkova et al. 2008; Hejzlarova et al. 2011). 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 (Havlíčková Karbanová et al. 2012; Braczynski et al. 2015). Based on the collective evidence, the c.317-2A>G variant is classified as pathogenic for mitochondrial complex V (ATP Synthase) deficiency, nuclear type. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 27, 2021	ACMG codes: PVS1; PS3; PS4; PM2; PP1; PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 22, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change affects an acceptor splice site in intron 2 of the TMEM70 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs183973249, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with mitochondrial complex V (ATP synthase) deficiency (PMID: 18953340, 26550569). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 540). Studies have shown that disruption of this splice site alters TMEM70 gene expression (PMID: 1895334). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2023	Variant summary: TMEM70 c.317-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Cizkova_2008). The variant allele was found at a frequency of 7.2e-05 in 250692 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TMEM70 causing Complex V Deficiency, Nuclear Type 2 (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.317-2A>G has been reported in the literature in multiple individuals affected with Complex V Deficiency, Nuclear Type 2 with co-segregation data providing strong evidence for causality (e.g., Cizkova_2008, Cameron_2011, Braczynski_2015, Torraco_2012). These data indicate that the variant is very likely to be associated with disease. 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. 12 ClinVar submitters (evaluation after 2014) have cited this variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	cDNA analysis found that c.317-2A>G leads to abnormal splicing and loss of normal TMEM70 transcript (PMID: 18953340); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29678161, 30096161, 24485043, 27649480, 31729175, 20335238, 21815885, 22433607, 26550569, 29502919, 31589614, 34440436, 20937241, 22986587, 20920610, 18953340) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2020	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been detected homozygous or compound heterozygous in multiple individuals with clinical features consistent with this disorder (PMID: 26550569, 24485043, 21815885, 18953340, and 20335238). This variant segregates with disease in multiple families (PMID: 26550569, 24485043, and 18953340). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 22433607, 20937241, and 18953340).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jul 19, 2022	PS4, PP3, PM2_SUP, PVS1_STR -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 30, 2022

ACMG categories: PVS1,PM2 -

TMEM70-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2023

The TMEM70 c.317-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be pathogenic in patients with neonatal mitochondrial encephalocardiomyopathy (Cízková et al. 2008. PubMed ID: 18953340; Honzík et al. 2010. PubMed ID: 20335238). 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). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-74893388-A-G). Variants that disrupt the consensus splice acceptor site in TMEM70 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Mar 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
GERP RS		5.3

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

Publications

LitVar

Other links and lift over

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