rs1261410358

Variant names:

• chr17-17992851-C-A
• rs1261410358
• NM_031294.4:c.531C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-17992851-C-A
• chr17-17992851-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.531C>A​(p.Phe177Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.594
• Publications: 1 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

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.531C>A	p.Phe177Leu	missense	Exon 6 of 14	NP_112584.3
	DRC3	NM_001130090.1		c.531C>A	p.Phe177Leu	missense	Exon 7 of 15	NP_001123562.1	B3KSC6
	DRC3	NM_001130091.2		c.531C>A	p.Phe177Leu	missense	Exon 7 of 14	NP_001123563.1	Q9H069-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC3	ENST00000399187.6	TSL:1 MANE Select	c.531C>A	p.Phe177Leu	missense	Exon 6 of 14	ENSP00000382140.1	Q9H069-1
	DRC3	ENST00000399182.5	TSL:1	c.531C>A	p.Phe177Leu	missense	Exon 6 of 13	ENSP00000382136.1	Q9H069-2
	DRC3	ENST00000584166.5	TSL:5	c.531C>A	p.Phe177Leu	missense	Exon 7 of 14	ENSP00000462661.1	Q9H069-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249270 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.47	T
PhyloP100		0.59
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.023	D
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.44		Loss of catalytic residue at F177 (P = 0.0667)
MVP		0.87
MPC		0.36
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.57
gMVP		0.68
Mutation Taster		=72/28	polymorphism

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: rs1261410358; hg19: chr17-17896165;