17-17997564-G-A

Position:

• chr17-17997564-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_031294.4(DRC3):​c.929G>A​(p.Arg310His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,610,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

Genes affected

DRC3 (HGNC:25384): (dynein regulatory complex subunit 3) Located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

DRC3 (HGNC:):

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018969655).
• BP6: Variant 17-17997564-G-A is Benign according to our data. Variant chr17-17997564-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2365963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC3	NM_031294.4	c.929G>A	p.Arg310His	missense_variant	9/14	ENST00000399187.6	NP_112584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRC3	ENST00000399187.6	c.929G>A	p.Arg310His	missense_variant	9/14	1	NM_031294.4	ENSP00000382140.1
DRC3	ENST00000399182.5	c.929G>A	p.Arg310His	missense_variant	9/13	1		ENSP00000382136.1
DRC3	ENST00000584166.5	c.929G>A	p.Arg310His	missense_variant	10/14	5		ENSP00000462661.1
DRC3	ENST00000583171.5	n.*91+4475G>A		intron_variant		3		ENSP00000464101.2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 58 AN: 243152 Hom.: 0 AF XY: 0.000189 AC XY: 25 AN XY: 132062

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000229

Gnomad SAS exome AF: 0.0000675

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000311 AC: 453 AN: 1457806 Hom.: 0 Cov.: 31 AF XY: 0.000314 AC XY: 228 AN XY: 725106

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.0000468

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000377

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000190 AC: 23

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.5
DANN	Benign	0.76
DEOGEN2	Benign	0.0011	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.14	T;.;.;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.090	N;N;.;N
REVEL	Benign	0.016
Sift	Benign	0.59	T;T;.;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.10
MVP		0.099
MPC		0.21
ClinPred		0.010	T
GERP RS		-0.66
Varity_R		0.029
gMVP		0.093

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

Publications

LitVar

Other links and lift over

dbSNP: rs199972472; hg19: chr17-17900878; COSMIC: COSV58262745; COSMIC: COSV58262745;