17-44315584-G-C

Variant names:

• chr17-44315584-G-C
• rs1482173695
• NM_001144825.2:c.928G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001144825.2(RUNDC3A):​c.928G>C​(p.Val310Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,509,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V310E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RUNDC3A NM_001144825.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55
• Publications: 0 publications found

Genes affected

RUNDC3A (HGNC:16984): (RUN domain containing 3A) Predicted to enable GTPase regulator activity. Predicted to be involved in positive regulation of cGMP-mediated signaling. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

RUNDC3A-AS1 (HGNC:51344): (RUNDC3A antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08470473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNDC3A	NM_001144825.2	c.928G>C	p.Val310Leu	missense_variant	Exon 8 of 11	ENST00000426726.8	NP_001138297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNDC3A	ENST00000426726.8	c.928G>C	p.Val310Leu	missense_variant	Exon 8 of 11	1	NM_001144825.2	ENSP00000410862.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000633 AC: 7 AN: 110618 AF XY: 0.0000492

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000103 AC: 14 AN: 1356818 Hom.: 0 Cov.: 33 AF XY: 0.00000897 AC XY: 6 AN XY: 668850

African (AFR) AF: 0.00 AC: 0 AN: 28528

American (AMR) AF: 0.000259 AC: 8 AN: 30834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24146

East Asian (EAS) AF: 0.00 AC: 0 AN: 30406

South Asian (SAS) AF: 0.00 AC: 0 AN: 74984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3954

European-Non Finnish (NFE) AF: 0.00000471 AC: 5 AN: 1060478

Other (OTH) AF: 0.0000178 AC: 1 AN: 56088

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.928G>C (p.V310L) alteration is located in exon 8 (coding exon 8) of the RUNDC3A gene. This alteration results from a G to C substitution at nucleotide position 928, causing the valine (V) at amino acid position 310 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	0.69
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;L
PhyloP100		2.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.80	N;.;N
REVEL	Benign	0.026
Sift	Benign	0.33	T;.;T
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.20	B;B;B
Vest4		0.15
MutPred		0.24		Gain of loop (P = 0.0051);.;Gain of loop (P = 0.0051);
MVP		0.10
MPC		1.2
ClinPred		0.059	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.34
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1482173695; hg19: chr17-42392952;