NM_017866.6:c.97C>G

Variant names:

• chr8-73976378-C-G
• rs145329086
• NM_017866.6:c.97C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017866.6(TMEM70):​c.97C>G​(p.Arg33Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,443,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R33R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM70 NM_017866.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.487
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045585364).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	NM_017866.6	MANE Select	c.97C>G	p.Arg33Gly	missense	Exon 1 of 3	NP_060336.3
	TMEM70	NM_001040613.3		c.97C>G	p.Arg33Gly	missense	Exon 1 of 3	NP_001035703.1
	TMEM70	NR_033334.2		n.184C>G		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.97C>G	p.Arg33Gly	missense	Exon 1 of 3	ENSP00000312599.5
	TMEM70	ENST00000517439.1	TSL:2	c.97C>G	p.Arg33Gly	missense	Exon 1 of 3	ENSP00000429467.1
	TMEM70	ENST00000416961.6	TSL:2	n.97C>G		non_coding_transcript_exon	Exon 1 of 4	ENSP00000407695.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000313 AC: 7 AN: 223984 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000973

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1443984 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 85442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5340

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110410

Other (OTH) AF: 0.00 AC: 0 AN: 59940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.8
DANN	Benign	0.96
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.49
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.0080
Sift	Benign	0.22	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.18		Loss of MoRF binding (P = 0.014)
MVP		0.048
MPC		0.32
ClinPred		0.018	T
GERP RS		-1.6
PromoterAI		0.0035	Neutral
Varity_R		0.070
gMVP		0.41
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs145329086; hg19: chr8-74888613;