rs1342146355

Variant names:

• chr17-17994390-C-G
• rs1342146355
• NM_031294.4:c.683C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-17994390-C-G
• chr17-17994390-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031294.4(DRC3):​c.683C>G​(p.Ala228Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. A228V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.453
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11653879).

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.683C>G	p.Ala228Gly	missense	Exon 7 of 14	NP_112584.3
	DRC3	NM_001130090.1		c.683C>G	p.Ala228Gly	missense	Exon 8 of 15	NP_001123562.1	B3KSC6
	DRC3	NM_001130091.2		c.683C>G	p.Ala228Gly	missense	Exon 8 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.683C>G	p.Ala228Gly	missense	Exon 7 of 14	ENSP00000382140.1	Q9H069-1
	DRC3	ENST00000399182.5	TSL:1	c.683C>G	p.Ala228Gly	missense	Exon 7 of 13	ENSP00000382136.1	Q9H069-2
	DRC3	ENST00000584166.5	TSL:5	c.683C>G	p.Ala228Gly	missense	Exon 8 of 14	ENSP00000462661.1	Q9H069-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.45
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.099
Sift	Benign	0.11	T
Sift4G	Benign	0.31	T
Polyphen		0.80	P
Vest4		0.18
MutPred		0.29		Gain of helix (P = 0.132)
MVP		0.42
MPC		0.37
ClinPred		0.63	D
GERP RS		2.1
Varity_R		0.077
gMVP		0.29

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: rs1342146355; hg19: chr17-17897704;