rs1815641175

Variant names:

• chr8-73976283-T-C
• rs1815641175
• NM_017866.6:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017866.6(TMEM70):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM70 NM_017866.6 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.52
• 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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 100 codons. Genomic position: 73978843. Lost 0.381 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-73976283-T-C is Pathogenic according to our data. Variant chr8-73976283-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 936698.Status of the report is criteria_provided_single_submitter, 1 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.2T>C	p.Met1?	start_lost	Exon 1 of 3	NP_060336.3
	TMEM70	NM_001040613.3		c.2T>C	p.Met1?	start_lost	Exon 1 of 3	NP_001035703.1	Q9BUB7-3
	TMEM70	NR_033334.2		n.89T>C		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.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENSP00000312599.5	Q9BUB7-1
	TMEM70	ENST00000517439.1	TSL:2	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENSP00000429467.1	Q9BUB7-3
	TMEM70	ENST00000416961.6	TSL:2	n.2T>C		non_coding_transcript_exon	Exon 1 of 4	ENSP00000407695.2	D4PHA6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.0011	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.63	T
PhyloP100		1.5
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.72
MutPred		0.84		Gain of catalytic residue at M1 (P = 0.0186)
MVP		0.55
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.33	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.62
Mutation Taster		=21/179	disease causing (ClinVar)

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: rs1815641175; hg19: chr8-74888518;