rs4584886

Variant names:

• chr17-17992891-C-G
• rs4584886
• NM_031294.4:c.571C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-17992891-C-G
• chr17-17992891-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031294.4(DRC3):​c.571C>G​(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• Publications: 46 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC3	NM_031294.4	c.571C>G	p.Arg191Gly	missense_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.571C>G	p.Arg191Gly	missense_variant	Exon 6 of 14	1	NM_031294.4	ENSP00000382140.1
DRC3	ENST00000399182.5	c.571C>G	p.Arg191Gly	missense_variant	Exon 6 of 13	1		ENSP00000382136.1
DRC3	ENST00000584166.5	c.571C>G	p.Arg191Gly	missense_variant	Exon 7 of 14	5		ENSP00000462661.1
DRC3	ENST00000583171.5	n.127C>G		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000464101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 19830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;.;.;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	-0.064	T
PhyloP100		3.5
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.6	D;D;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D;D;.;D
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.41
MutPred		0.46		Loss of stability (P = 0.046);Loss of stability (P = 0.046);Loss of stability (P = 0.046);Loss of stability (P = 0.046);
MVP		0.78
MPC		0.59
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.57
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4584886; hg19: chr17-17896205;