rs554588749

Variant names:

• chr17-17992894-C-T
• rs554588749
• NM_031294.4:c.574C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_031294.4(DRC3):​c.574C>T​(p.Arg192Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28653628).

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.574C>T	p.Arg192Cys	missense	Exon 6 of 14	NP_112584.3
	DRC3	NM_001130090.1		c.574C>T	p.Arg192Cys	missense	Exon 7 of 15	NP_001123562.1	B3KSC6
	DRC3	NM_001130091.2		c.574C>T	p.Arg192Cys	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.574C>T	p.Arg192Cys	missense	Exon 6 of 14	ENSP00000382140.1	Q9H069-1
	DRC3	ENST00000399182.5	TSL:1	c.574C>T	p.Arg192Cys	missense	Exon 6 of 13	ENSP00000382136.1	Q9H069-2
	DRC3	ENST00000584166.5	TSL:5	c.574C>T	p.Arg192Cys	missense	Exon 7 of 14	ENSP00000462661.1	Q9H069-2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249240 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461680 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727114

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: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74450

African (AFR) AF: 0.0000481 AC: 2 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

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	Benign	0.11
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0074	T
Eigen	Benign	0.028
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.77	T
PhyloP100		2.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.17
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.036	D
Polyphen		0.012	B
Vest4		0.23
MutPred		0.49		Loss of disorder (P = 0.0599)
MVP		0.59
MPC		0.25
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.54
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs554588749; hg19: chr17-17896208; COSMIC: COSV100572595; COSMIC: COSV100572595;