rs139864454

Variant names:

• chr8-73981372-T-C
• rs139864454
• NM_017866.6:c.534T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_017866.6(TMEM70):​c.534T>C​(p.Thr178Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,614,216 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (7 hom.)
• Consequence: TMEM70 NM_017866.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.323
• 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, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 8-73981372-T-C is Benign according to our data. Variant chr8-73981372-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 363691.
• BP7: Synonymous conserved (PhyloP=0.323 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000633 (925/1461866) while in subpopulation SAS AF = 0.000696 (60/86258). AF 95% confidence interval is 0.000554. There are 7 homozygotes in GnomAdExome4. There are 468 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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.534T>C	p.Thr178Thr	synonymous	Exon 3 of 3	NP_060336.3
	TMEM70	NM_001040613.3		c.*224T>C		3_prime_UTR	Exon 3 of 3	NP_001035703.1
	TMEM70	NR_033334.2		n.714T>C		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.534T>C	p.Thr178Thr	synonymous	Exon 3 of 3	ENSP00000312599.5
	TMEM70	ENST00000416961.6	TSL:2	n.*291T>C		non_coding_transcript_exon	Exon 4 of 4	ENSP00000407695.2
	TMEM70	ENST00000519551.1	TSL:2	n.425T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00159 AC: 399 AN: 251454 AF XY: 0.00156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000633 AC: 925 AN: 1461866 Hom.: 7 Cov.: 33 AF XY: 0.000644 AC XY: 468 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86258

European-Finnish (FIN) AF: 0.0148 AC: 793 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1112002

Other (OTH) AF: 0.000381 AC: 23 AN: 60394

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74508

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.2
DANN	Benign	0.74
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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: rs139864454; hg19: chr8-74893607; COSMIC: COSV56487729; COSMIC: COSV56487729;