NM_031294.4:c.161A>G

Variant names:

• chr17-17983828-A-G
• rs187632732
• NM_031294.4:c.161A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031294.4(DRC3):​c.161A>G​(p.Asn54Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,607,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DRC3 NM_031294.4 missense, splice_region
• Scores: Splicing: ADA: 0.001317
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35
• Publications: 0 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

LOC107984989 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21917135).

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.161A>G	p.Asn54Ser	missense splice_region	Exon 4 of 14	NP_112584.3
	DRC3	NM_001130090.1		c.161A>G	p.Asn54Ser	missense splice_region	Exon 5 of 15	NP_001123562.1	B3KSC6
	DRC3	NM_001130091.2		c.161A>G	p.Asn54Ser	missense splice_region	Exon 5 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.161A>G	p.Asn54Ser	missense splice_region	Exon 4 of 14	ENSP00000382140.1	Q9H069-1
	DRC3	ENST00000399182.5	TSL:1	c.161A>G	p.Asn54Ser	missense splice_region	Exon 4 of 13	ENSP00000382136.1	Q9H069-2
	DRC3	ENST00000584166.5	TSL:5	c.161A>G	p.Asn54Ser	missense splice_region	Exon 5 of 14	ENSP00000462661.1	Q9H069-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 248342 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

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: 0.000166

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1455462 Hom.: 0 Cov.: 28 AF XY: 0.00000828 AC XY: 6 AN XY: 724474

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.000202 AC: 9 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106712

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

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	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.22	T
PhyloP100		3.4
Sift4G	Benign	0.13	T
MVP		0.67
ClinPred		0.35	T
GERP RS		5.2
Varity_R		0.31
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.010
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: rs187632732; hg19: chr17-17887142;