17-17985235-T-C

Variant names:

• chr17-17985235-T-C
• rs4459604
• NM_031294.4:c.277+1291T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031294.4(DRC3):​c.277+1291T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 152,088 control chromosomes in the GnomAD database, including 19,132 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (19132 hom., cov: 32)
• Consequence: DRC3 NM_031294.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.892
• Publications: 14 publications found

Genes affected

DRC3 (HGNC:25384): (dynein regulatory complex subunit 3) Located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

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

LOC107984989 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031294.4. 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
	DRC3	NM_031294.4	MANE Select	c.277+1291T>C		intron	N/A	NP_112584.3
	DRC3	NM_001130090.1		c.277+1291T>C		intron	N/A	NP_001123562.1
	DRC3	NM_001130091.2		c.277+1291T>C		intron	N/A	NP_001123563.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC3	ENST00000399187.6	TSL:1 MANE Select	c.277+1291T>C		intron	N/A	ENSP00000382140.1
	DRC3	ENST00000399182.5	TSL:1	c.277+1291T>C		intron	N/A	ENSP00000382136.1
	DRC3	ENST00000584166.5	TSL:5	c.277+1291T>C		intron	N/A	ENSP00000462661.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71861 AN: 151970 Hom.: 19098 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.453

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.473 AC: 71949 AN: 152088 Hom.: 19132 Cov.: 32 AF XY: 0.484 AC XY: 35973 AN XY: 74348

African (AFR) AF: 0.642 AC: 26643 AN: 41482

American (AMR) AF: 0.527 AC: 8045 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1442 AN: 3470

East Asian (EAS) AF: 0.900 AC: 4661 AN: 5180

South Asian (SAS) AF: 0.723 AC: 3484 AN: 4822

European-Finnish (FIN) AF: 0.406 AC: 4296 AN: 10570

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21928 AN: 67972

Other (OTH) AF: 0.453 AC: 955 AN: 2110

Alfa AF: 0.383 Hom.: 15664

Bravo AF: 0.487

Asia WGS AF: 0.740 AC: 2570 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.92
DANN	Benign	0.63
PhyloP100		-0.89
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: rs4459604; hg19: chr17-17888549;