NM_031294.4:c.1326+2596T>C

Variant names:

• chr17-18009743-T-C
• rs6502632
• NM_031294.4:c.1326+2596T>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.1326+2596T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 152,028 control chromosomes in the GnomAD database, including 15,121 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 0.43 (15121 hom., cov: 32)
• Consequence: DRC3 NM_031294.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.304
• Publications: 8 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC3	NM_031294.4	MANE Select	c.1326+2596T>C		intron	N/A	NP_112584.3
	DRC3	NM_001130090.1		c.1326+2596T>C		intron	N/A	NP_001123562.1	B3KSC6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC3	ENST00000399187.6	TSL:1 MANE Select	c.1326+2596T>C		intron	N/A	ENSP00000382140.1	Q9H069-1
	DRC3	ENST00000583171.5	TSL:3	n.*418+2596T>C		intron	N/A	ENSP00000464101.2	J3QR90
	DRC3	ENST00000887428.1		c.1383+2596T>C		intron	N/A	ENSP00000557487.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64664 AN: 151910 Hom.: 15106 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.421

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

GnomAD4 genome AF: 0.426 AC: 64713 AN: 152028 Hom.: 15121 Cov.: 32 AF XY: 0.439 AC XY: 32604 AN XY: 74318

African (AFR) AF: 0.477 AC: 19781 AN: 41444

American (AMR) AF: 0.508 AC: 7760 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3468

East Asian (EAS) AF: 0.909 AC: 4692 AN: 5164

South Asian (SAS) AF: 0.722 AC: 3479 AN: 4820

European-Finnish (FIN) AF: 0.407 AC: 4306 AN: 10580

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21878 AN: 67962

Other (OTH) AF: 0.421 AC: 889 AN: 2110

Alfa AF: 0.394 Hom.: 2665

Bravo AF: 0.434

Asia WGS AF: 0.725 AC: 2519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.83
PhyloP100		-0.30
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: rs6502632; hg19: chr17-17913057;