17-17992891-C-T

Position:

• chr17-17992891-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000399187.6(DRC3):​c.571C>T​(p.Arg191Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,078 control chromosomes in the GnomAD database, including 126,421 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (13438 hom., cov: 32)
  • Exomes 𝑓: 0.37 (112983 hom.)
• Consequence: DRC3 ENST00000399187.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0401418E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC3	NM_031294.4	c.571C>T	p.Arg191Trp	missense_variant	6/14	ENST00000399187.6	NP_112584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRC3	ENST00000399187.6	c.571C>T	p.Arg191Trp	missense_variant	6/14	1	NM_031294.4	ENSP00000382140	P1

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61087 AN: 151898 Hom.: 13431 Cov.: 32

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.404

GnomAD3 exomes AF: 0.467 AC: 116249 AN: 249176 Hom.: 31332 AF XY: 0.470 AC XY: 63594 AN XY: 135168

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.880

Gnomad SAS exome AF: 0.711

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.368 AC: 537712 AN: 1461062 Hom.: 112983 Cov.: 37 AF XY: 0.378 AC XY: 274985 AN XY: 726842

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.587

Gnomad4 ASJ exome AF: 0.415

Gnomad4 EAS exome AF: 0.866

Gnomad4 SAS exome AF: 0.706

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.402 AC: 61128 AN: 152016 Hom.: 13438 Cov.: 32 AF XY: 0.416 AC XY: 30884 AN XY: 74328

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.719

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.404

Alfa AF: 0.345 Hom.: 12777

Bravo AF: 0.408

TwinsUK AF: 0.301 AC: 1117

ALSPAC AF: 0.300 AC: 1157

ESP6500AA AF: 0.400 AC: 1688

ESP6500EA AF: 0.326 AC: 2759

ExAC AF: 0.461 AC: 55756

Asia WGS AF: 0.704 AC: 2447 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.341

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;.;.;T
MetaRNN	Benign	0.0000010	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.00012	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-6.5	D;D;.;D
REVEL	Benign	0.22
Sift	Uncertain	0.017	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.19
MPC		0.69
ClinPred		0.050	T
GERP RS		3.0
Varity_R		0.50
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs4584886; hg19: chr17-17896205;