NM_145691.4:c.616+191T>C

Variant names:

• chr17-18021554-A-G
• rs9896837
• NM_145691.4:c.616+191T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145691.4(ATPAF2):​c.616+191T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 647,418 control chromosomes in the GnomAD database, including 65,935 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13474 hom., cov: 32)
  • Exomes 𝑓: 0.43 (52461 hom.)
• Consequence: ATPAF2 NM_145691.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.639
• Publications: 13 publications found

Genes affected

ATPAF2 (HGNC:18802): (ATP synthase mitochondrial F1 complex assembly factor 2) This gene encodes an assembly factor for the F(1) component of the mitochondrial ATP synthase. This protein binds specifically to the F1 alpha subunit and is thought to prevent this subunit from forming nonproductive homooligomers during enzyme assembly. This gene is located within the Smith-Magenis syndrome region on chromosome 17. An alternatively spliced transcript variant has been described, but its biological validity has not been determined. [provided by RefSeq, Jul 2008]

ATPAF2 Gene-Disease associations (from GenCC):

• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 1

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-18021554-A-G is Benign according to our data. Variant chr17-18021554-A-G is described in ClinVar as Benign. ClinVar VariationId is 669688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATPAF2	NM_145691.4	MANE Select	c.616+191T>C		intron	N/A	NP_663729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATPAF2	ENST00000474627.8	TSL:1 MANE Select	c.616+191T>C		intron	N/A	ENSP00000417190.2
	ATPAF2	ENST00000462733.5	TSL:1	n.*34-316T>C		intron	N/A	ENSP00000463920.1
	ATPAF2	ENST00000465337.2	TSL:5	n.160T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61173 AN: 151950 Hom.: 13467 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.427 AC: 211451 AN: 495350 Hom.: 52461 Cov.: 5 AF XY: 0.441 AC XY: 116559 AN XY: 264268

African (AFR) AF: 0.412 AC: 5746 AN: 13946

American (AMR) AF: 0.572 AC: 15241 AN: 26628

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 6443 AN: 15584

East Asian (EAS) AF: 0.862 AC: 27044 AN: 31370

South Asian (SAS) AF: 0.707 AC: 36976 AN: 52292

European-Finnish (FIN) AF: 0.372 AC: 12418 AN: 33352

Middle Eastern (MID) AF: 0.433 AC: 911 AN: 2104

European-Non Finnish (NFE) AF: 0.326 AC: 95310 AN: 292314

Other (OTH) AF: 0.409 AC: 11362 AN: 27760

GnomAD4 genome AF: 0.403 AC: 61214 AN: 152068 Hom.: 13474 Cov.: 32 AF XY: 0.416 AC XY: 30927 AN XY: 74340

African (AFR) AF: 0.407 AC: 16858 AN: 41444

American (AMR) AF: 0.495 AC: 7571 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1435 AN: 3468

East Asian (EAS) AF: 0.869 AC: 4494 AN: 5172

South Asian (SAS) AF: 0.718 AC: 3461 AN: 4820

European-Finnish (FIN) AF: 0.398 AC: 4219 AN: 10588

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21835 AN: 67972

Other (OTH) AF: 0.405 AC: 855 AN: 2110

Alfa AF: 0.386 Hom.: 2087

Bravo AF: 0.409

Asia WGS AF: 0.704 AC: 2447 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.63
PhyloP100		0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs9896837; hg19: chr17-17924868;