8-73982335-G-A

Position:

• chr8-73982335-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017866.6(TMEM70):​c.*714G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00183 in 682,186 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: TMEM70 NM_017866.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.36

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]

RPS20P21 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 8-73982335-G-A is Benign according to our data. Variant chr8-73982335-G-A is described in ClinVar as [Benign]. Clinvar id is 363709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00503 (766/152226) while in subpopulation AFR AF= 0.0165 (685/41534). 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.*714G>A		3_prime_UTR_variant	3/3	ENST00000312184.6	NP_060336.3
TMEM70	NM_001040613.3	c.*1187G>A		3_prime_UTR_variant	3/3		NP_001035703.1
TMEM70	NR_033334.2	n.1677G>A		non_coding_transcript_exon_variant	4/4
RPS20P21		n.73982335G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM70	ENST00000312184.6	c.*714G>A		3_prime_UTR_variant	3/3	1	NM_017866.6	ENSP00000312599.5
RPS20P21	ENST00000466859.2	n.211G>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 765 AN: 152106 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00173 AC: 411 AN: 237756 Hom.: 1 AF XY: 0.00145 AC XY: 188 AN XY: 129592

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.000703

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000913 AC: 484 AN: 529960 Hom.: 2 Cov.: 6 AF XY: 0.000822 AC XY: 240 AN XY: 292066

Gnomad4 AFR exome AF: 0.0144

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.000960

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.0000742

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152226 Hom.: 4 Cov.: 33 AF XY: 0.00533 AC XY: 397 AN XY: 74424

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00327

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: 0.00283 Hom.: 0

Bravo AF: 0.00539

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.60
CADD	Benign	4.0
DANN	Benign	0.79

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: rs116019026; hg19: chr8-74894570;