Genetic Variant TMEM70:n.247T>A (chr8-73975891-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000520167.5(TMEM70):n.247T>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 164,072 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 49 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

TMEM70
ENST00000520167.5 non_coding_transcript_exon

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.108

Publications

0 publications found

Variant links:

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

TMEM70 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 8-73975891-T-A is Benign according to our data. Variant chr8-73975891-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1212724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2632/152106) while in subpopulation NFE AF = 0.025 (1699/67972). AF 95% confidence interval is 0.024. There are 49 homozygotes in GnomAd4. There are 1254 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000520167.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000520167.5	TSL:2	n.247T>A		non_coding_transcript_exon	Exon 2 of 4
	TMEM70	ENST00000523794.1	TSL:3	n.504T>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2632

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00413

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.0556

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00664

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0225

GnomAD4 exome

AF:

0.00134

AC:

AN:

11966

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

AN XY:

6284

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

732

American (AMR)

AF:

0.00

AC:

AN:

826

Ashkenazi Jewish (ASJ)

AF:

0.00127

AC:

AN:

790

East Asian (EAS)

AF:

0.00

AC:

AN:

280

South Asian (SAS)

AF:

0.00

AC:

AN:

1702

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00160

AC:

AN:

6240

Other (OTH)

AF:

0.00362

AC:

AN:

828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000185586), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.397

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0173

AC:

2632

AN:

152106

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1254

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41496

American (AMR)

AF:

0.0177

AC:

271

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0556

AC:

193

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00664

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0157

AC:

166

AN:

10572

Middle Eastern (MID)

AF:

0.0651

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0250

AC:

1699

AN:

67972

Other (OTH)

AF:

0.0228

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0266

Hom.:

Bravo

AF:

0.0171

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.0

(source)

DANN

Benign

0.83

PhyloP100

0.11

PromoterAI

0.027

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over