rs1554599426

Variant names:

• chr8-73981337-G-A
• rs1554599426
• NM_017866.6:c.499G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017866.6(TMEM70):​c.499G>A​(p.Val167Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V167A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM70 NM_017866.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM70	NM_017866.6	c.499G>A	p.Val167Ile	missense_variant	Exon 3 of 3	ENST00000312184.6	NP_060336.3
TMEM70	NR_033334.2	n.679G>A		non_coding_transcript_exon_variant	Exon 4 of 4
TMEM70	NM_001040613.3	c.*189G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001035703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6	c.499G>A	p.Val167Ile	missense_variant	Exon 3 of 3	1	NM_017866.6	ENSP00000312599.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 Uncertain:1

Jul 04, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant has uncertain impact on TMEM70 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a TMEM70-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 167 of the TMEM70 protein (p.Val167Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.30
Sift	Benign	0.042	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.23
MutPred		0.79		Gain of methylation at K164 (P = 0.0981);
MVP		0.56
MPC		0.76
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.77
Mutation Taster		=77/23	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: rs1554599426; hg19: chr8-74893572;