17-18006186-A-C

Position:

• chr17-18006186-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031294.4(DRC3):​c.1135A>C​(p.Thr379Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DRC3 NM_031294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.258

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2316162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC3	NM_031294.4	c.1135A>C	p.Thr379Pro	missense_variant	11/14	ENST00000399187.6	NP_112584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRC3	ENST00000399187.6	c.1135A>C	p.Thr379Pro	missense_variant	11/14	1	NM_031294.4	ENSP00000382140.1
DRC3	ENST00000399182.5	c.1135A>C	p.Thr379Pro	missense_variant	11/13	1		ENSP00000382136.1
DRC3	ENST00000584166.5	c.1135A>C	p.Thr379Pro	missense_variant	12/14	5		ENSP00000462661.1
DRC3	ENST00000583171.5	n.*227A>C		non_coding_transcript_exon_variant	3/6	3		ENSP00000464101.2
DRC3	ENST00000583171.5	n.*227A>C		3_prime_UTR_variant	3/6	3		ENSP00000464101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456496 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2024

The c.1135A>C (p.T379P) alteration is located in exon 12 (coding exon 9) of the DRC3 gene. This alteration results from a A to C substitution at nucleotide position 1135, causing the threonine (T) at amino acid position 379 to be replaced by a proline (P). 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	0.70
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.074	T;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.60	T;.;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;N;.;N
REVEL	Benign	0.21
Sift	Benign	0.069	T;T;.;T
Sift4G	Uncertain	0.055	T;T;T;T
Polyphen		0.90	P;P;D;D
Vest4		0.47
MutPred		0.43		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.47
MPC		0.38
ClinPred		0.44	T
GERP RS		1.9
Varity_R		0.43
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17909500;