chr8-73976259-C-T

Variant names:

• chr8-73976259-C-T
• rs2306486
• ENST00000312184:c.-23C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017866.6(TMEM70):​c.-23C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,591,254 control chromosomes in the GnomAD database, including 71,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4999 hom., cov: 33)
  • Exomes 𝑓: 0.30 (66400 hom.)
• Consequence: TMEM70 NM_017866.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.81

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 (BayesDel_noAF=-0.74).
• BP6: Variant 8-73976259-C-T is Benign according to our data. Variant chr8-73976259-C-T is described in ClinVar as [Benign]. Clinvar id is 363687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-73976259-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM70	NM_017866.6	c.-23C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	ENST00000312184.6	NP_060336.3
TMEM70	NM_017866.6	c.-23C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000312184.6	NP_060336.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184	c.-23C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	1	NM_017866.6	ENSP00000312599.5
TMEM70	ENST00000312184	c.-23C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_017866.6	ENSP00000312599.5

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37474 AN: 152004 Hom.: 4996 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.272 AC: 60696 AN: 222958 Hom.: 8581 AF XY: 0.278 AC XY: 34110 AN XY: 122576

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.318

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.299 AC: 430213 AN: 1439132 Hom.: 66400 Cov.: 31 AF XY: 0.300 AC XY: 214856 AN XY: 716092

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.246 AC: 37488 AN: 152122 Hom.: 4999 Cov.: 33 AF XY: 0.247 AC XY: 18388 AN XY: 74374

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.223

Alfa AF: 0.257 Hom.: 1621

Bravo AF: 0.235

Asia WGS AF: 0.237 AC: 826 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.7
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs2306486; hg19: chr8-74888494; COSMIC: COSV53023236; COSMIC: COSV53023236;