17-17994425-T-C

Variant names:

• chr17-17994425-T-C
• rs4924832
• NM_031294.4:c.711+7T>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.711+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,550,572 control chromosomes in the GnomAD database, including 125,413 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.44 (16363 hom., cov: 32)
  • Exomes 𝑓: 0.37 (109050 hom.)
• Consequence: DRC3 NM_031294.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005302
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 18 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 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.711+7T>C		splice_region intron	N/A	NP_112584.3
	DRC3	NM_001130090.1		c.711+7T>C		splice_region intron	N/A	NP_001123562.1
	DRC3	NM_001130091.2		c.711+7T>C		splice_region 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.711+7T>C		splice_region intron	N/A	ENSP00000382140.1
	DRC3	ENST00000399182.5	TSL:1	c.711+7T>C		splice_region intron	N/A	ENSP00000382136.1
	DRC3	ENST00000584166.5	TSL:5	c.711+7T>C		splice_region intron	N/A	ENSP00000462661.1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67113 AN: 151926 Hom.: 16340 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.901

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.491 AC: 75697 AN: 154074 AF XY: 0.499

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.907

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.446

GnomAD4 exome AF: 0.369 AC: 516684 AN: 1398528 Hom.: 109050 Cov.: 35 AF XY: 0.379 AC XY: 261724 AN XY: 689818

African (AFR) AF: 0.539 AC: 17034 AN: 31592

American (AMR) AF: 0.582 AC: 20757 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 10484 AN: 25170

East Asian (EAS) AF: 0.888 AC: 31741 AN: 35732

South Asian (SAS) AF: 0.708 AC: 56045 AN: 79210

European-Finnish (FIN) AF: 0.383 AC: 18557 AN: 48486

Middle Eastern (MID) AF: 0.414 AC: 2356 AN: 5696

European-Non Finnish (NFE) AF: 0.311 AC: 335617 AN: 1078926

Other (OTH) AF: 0.415 AC: 24093 AN: 58024

GnomAD4 genome AF: 0.442 AC: 67177 AN: 152044 Hom.: 16363 Cov.: 32 AF XY: 0.454 AC XY: 33763 AN XY: 74318

African (AFR) AF: 0.535 AC: 22179 AN: 41450

American (AMR) AF: 0.511 AC: 7810 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1438 AN: 3470

East Asian (EAS) AF: 0.901 AC: 4657 AN: 5168

South Asian (SAS) AF: 0.722 AC: 3482 AN: 4826

European-Finnish (FIN) AF: 0.407 AC: 4308 AN: 10574

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

European-Non Finnish (NFE) AF: 0.322 AC: 21897 AN: 67954

Other (OTH) AF: 0.435 AC: 918 AN: 2110

Alfa AF: 0.374 Hom.: 7182

Bravo AF: 0.452

Asia WGS AF: 0.731 AC: 2540 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.30
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.050
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: rs4924832; hg19: chr17-17897739;