8-73976259-C-T

Variant names:

• chr8-73976259-C-T
• rs2306486
• NM_017866.6:c.-23C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 363687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

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.-23C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_060336.3
	TMEM70	NM_017866.6	MANE Select	c.-23C>T		5_prime_UTR	Exon 1 of 3	NP_060336.3
	TMEM70	NM_001040613.3		c.-23C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001035703.1	Q9BUB7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.-23C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000312599.5	Q9BUB7-1
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.-23C>T		5_prime_UTR	Exon 1 of 3	ENSP00000312599.5	Q9BUB7-1
	TMEM70	ENST00000517439.1	TSL:2	c.-23C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000429467.1	Q9BUB7-3

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

GnomAD2 exomes AF: 0.272 AC: 60696 AN: 222958 AF XY: 0.278

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 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

African (AFR) AF: 0.140 AC: 4652 AN: 33324

American (AMR) AF: 0.256 AC: 11172 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3292 AN: 25910

East Asian (EAS) AF: 0.178 AC: 7012 AN: 39326

South Asian (SAS) AF: 0.320 AC: 27207 AN: 85082

European-Finnish (FIN) AF: 0.338 AC: 13301 AN: 39374

Middle Eastern (MID) AF: 0.214 AC: 1159 AN: 5426

European-Non Finnish (NFE) AF: 0.312 AC: 345848 AN: 1107150

Other (OTH) AF: 0.277 AC: 16570 AN: 59842

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

African (AFR) AF: 0.148 AC: 6162 AN: 41552

American (AMR) AF: 0.228 AC: 3482 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3472

East Asian (EAS) AF: 0.190 AC: 987 AN: 5182

South Asian (SAS) AF: 0.303 AC: 1462 AN: 4830

European-Finnish (FIN) AF: 0.332 AC: 3509 AN: 10558

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.302 AC: 20533 AN: 67930

Other (OTH) AF: 0.223 AC: 470 AN: 2112

Alfa AF: 0.255 Hom.: 1633

Bravo AF: 0.235

Asia WGS AF: 0.237 AC: 826 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.7
DANN	Benign	0.93
PhyloP100		-1.8
PromoterAI		-0.091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=300/0	polymorphism (auto)

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