NM_031294.4:c.575G>C

Variant names:

• chr17-17992895-G-C
• NM_031294.4:c.575G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031294.4(DRC3):​c.575G>C​(p.Arg192Pro) 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 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC3	NM_031294.4	c.575G>C	p.Arg192Pro	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.575G>C	p.Arg192Pro	missense_variant	Exon 6 of 14	1	NM_031294.4	ENSP00000382140.1
DRC3	ENST00000399182.5	c.575G>C	p.Arg192Pro	missense_variant	Exon 6 of 13	1		ENSP00000382136.1
DRC3	ENST00000584166.5	c.575G>C	p.Arg192Pro	missense_variant	Exon 7 of 14	5		ENSP00000462661.1
DRC3	ENST00000583171.5	n.131G>C		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000464101.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T;T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;.;.;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.62	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;N;.;N
REVEL	Benign	0.28
Sift	Uncertain	0.028	D;D;.;D
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.97	D;D;D;D
Vest4		0.46
MutPred		0.48		Loss of stability (P = 0.0482);Loss of stability (P = 0.0482);Loss of stability (P = 0.0482);Loss of stability (P = 0.0482);
MVP		0.83
MPC		0.72
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.51
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17896209;