8-73981522-C-G

Position:

• chr8-73981522-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017866.6(TMEM70):​c.684C>G​(p.Asn228Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,790 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (6 hom.)
• Consequence: TMEM70 NM_017866.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.436

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00697127).
• BP6: Variant 8-73981522-C-G is Benign according to our data. Variant chr8-73981522-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 137679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-73981522-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00504 (767/152288) while in subpopulation AFR AF= 0.0165 (687/41552). AF 95% confidence interval is 0.0155. There are 4 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM70	NM_017866.6	c.684C>G	p.Asn228Lys	missense_variant	3/3	ENST00000312184.6	NP_060336.3
TMEM70	NM_001040613.3	c.*374C>G		3_prime_UTR_variant	3/3		NP_001035703.1
TMEM70	NR_033334.2	n.864C>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6	c.684C>G	p.Asn228Lys	missense_variant	3/3	1	NM_017866.6	ENSP00000312599	P1
TMEM70	ENST00000416961.6	c.*441C>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	2		ENSP00000407695
TMEM70	ENST00000519551.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 766 AN: 152170 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00169 AC: 425 AN: 251258 Hom.: 1 AF XY: 0.00142 AC XY: 193 AN XY: 135800

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000637 AC: 931 AN: 1461502 Hom.: 6 Cov.: 32 AF XY: 0.000601 AC XY: 437 AN XY: 727084

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00504 AC: 767 AN: 152288 Hom.: 4 Cov.: 33 AF XY: 0.00533 AC XY: 397 AN XY: 74476

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.00539

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex V (ATP synthase) deficiency nuclear type 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.6
DANN	Benign	0.93
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.10
Sift	Benign	0.050	D
Sift4G	Benign	0.28	T
Polyphen		0.71	P
Vest4		0.38
MutPred		0.24		Gain of methylation at N228 (P = 0.0019);
MVP		0.31
MPC		0.49
ClinPred		0.045	T
GERP RS		0.39
Varity_R		0.098
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs35564486; hg19: chr8-74893757;