chr17-17992776-C-T

Variant names:

• chr17-17992776-C-T
• rs4368210
• NM_031294.4:c.456C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_031294.4(DRC3):​c.456C>T​(p.Leu152Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,612,222 control chromosomes in the GnomAD database, including 126,249 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 0.40 (13438 hom., cov: 31)
  • Exomes 𝑓: 0.37 (112811 hom.)
• Consequence: DRC3 NM_031294.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC3	NM_031294.4	c.456C>T	p.Leu152Leu	synonymous_variant	Exon 6 of 14	ENST00000399187.6	NP_112584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRC3	ENST00000399187.6	c.456C>T	p.Leu152Leu	synonymous_variant	Exon 6 of 14	1	NM_031294.4	ENSP00000382140.1
DRC3	ENST00000399182.5	c.456C>T	p.Leu152Leu	synonymous_variant	Exon 6 of 13	1		ENSP00000382136.1
DRC3	ENST00000584166.5	c.456C>T	p.Leu152Leu	synonymous_variant	Exon 7 of 14	5		ENSP00000462661.1
DRC3	ENST00000583171.5	n.12C>T		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000464101.2

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61088 AN: 151788 Hom.: 13431 Cov.: 31

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.406

GnomAD2 exomes AF: 0.466 AC: 115311 AN: 247446 AF XY: 0.470

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.880

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.368 AC: 537321 AN: 1460314 Hom.: 112811 Cov.: 36 AF XY: 0.378 AC XY: 274745 AN XY: 726392

African (AFR) AF: 0.410 AC: 13722 AN: 33456

American (AMR) AF: 0.587 AC: 26136 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10818 AN: 26066

East Asian (EAS) AF: 0.865 AC: 34316 AN: 39678

South Asian (SAS) AF: 0.706 AC: 60851 AN: 86166

European-Finnish (FIN) AF: 0.375 AC: 19980 AN: 53306

Middle Eastern (MID) AF: 0.405 AC: 2336 AN: 5766

European-Non Finnish (NFE) AF: 0.311 AC: 345042 AN: 1111014

Other (OTH) AF: 0.400 AC: 24120 AN: 60330

GnomAD4 genome AF: 0.402 AC: 61128 AN: 151908 Hom.: 13438 Cov.: 31 AF XY: 0.416 AC XY: 30868 AN XY: 74234

African (AFR) AF: 0.406 AC: 16811 AN: 41382

American (AMR) AF: 0.495 AC: 7551 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1438 AN: 3472

East Asian (EAS) AF: 0.869 AC: 4491 AN: 5166

South Asian (SAS) AF: 0.718 AC: 3457 AN: 4814

European-Finnish (FIN) AF: 0.399 AC: 4209 AN: 10554

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

European-Non Finnish (NFE) AF: 0.321 AC: 21829 AN: 67938

Other (OTH) AF: 0.405 AC: 856 AN: 2112

Alfa AF: 0.356 Hom.: 15842

Bravo AF: 0.409

Asia WGS AF: 0.704 AC: 2447 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.1
DANN	Benign	0.66
PhyloP100		0.27
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: rs4368210; hg19: chr17-17896090; COSMIC: COSV58263374; COSMIC: COSV58263374;