Genetic Variant NM_031294.4:c.531C>A (chr17-17992851-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031294.4(DRC3):c.531C>A(p.Phe177Leu) 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 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DRC3
NM_031294.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.594

Variant links:

Genes affected

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

DRC3 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC3	NM_031294.4 link	c.531C>A	p.Phe177Leu	missense_variant	Exon 6 of 14	ENST00000399187.6	NP_112584.3	Q9H069-1B3KSC6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DRC3	ENST00000399187.6 link	c.531C>A	p.Phe177Leu	missense_variant	Exon 6 of 14	1	NM_031294.4	ENSP00000382140.1	Q9H069-1
DRC3	ENST00000399182.5 link	c.531C>A	p.Phe177Leu	missense_variant	Exon 6 of 13	1		ENSP00000382136.1	Q9H069-2
DRC3	ENST00000584166.5 link	c.531C>A	p.Phe177Leu	missense_variant	Exon 7 of 14	5		ENSP00000462661.1	Q9H069-2
DRC3	ENST00000583171.5 link	n.87C>A		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000464101.2	J3QR90

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249270

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.531C>A (p.F177L) alteration is located in exon 7 (coding exon 4) of the DRC3 gene. This alteration results from a C to A substitution at nucleotide position 531, causing the phenylalanine (F) at amino acid position 177 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

T;T;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.67

T;.;.;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Benign

-0.47

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.6

D;D;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.023

D;D;.;D

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.99

D;D;D;D

Vest4

0.62

MutPred

0.44

Loss of catalytic residue at F177 (P = 0.0667);Loss of catalytic residue at F177 (P = 0.0667);Loss of catalytic residue at F177 (P = 0.0667);Loss of catalytic residue at F177 (P = 0.0667);

MVP

0.87

MPC

0.36

ClinPred

0.99

GERP RS

3.9

Varity_R

0.57

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over