Genetic Variant RUNDC3A:p.Glu354Asp (chr17-44316493-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001144825.2(RUNDC3A):c.1062G>C(p.Glu354Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RUNDC3A
NM_001144825.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.951

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.077771604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNDC3A	NM_001144825.2 link	c.1062G>C	p.Glu354Asp	missense_variant	Exon 9 of 11	ENST00000426726.8	NP_001138297.1	Q59EK9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNDC3A	ENST00000426726.8 link	c.1062G>C	p.Glu354Asp	missense_variant	Exon 9 of 11	1	NM_001144825.2	ENSP00000410862.2		Q59EK9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000821

AC:

AN:

243586

AF XY:

0.00000750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460382

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000126

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111672

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1062G>C (p.E354D) alteration is located in exon 9 (coding exon 9) of the RUNDC3A gene. This alteration results from a G to C substitution at nucleotide position 1062, causing the glutamic acid (E) at amino acid position 354 to be replaced by an aspartic acid (D). 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

Benign

0.069

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.078

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;N

PhyloP100

0.95

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.71

N;.;N

REVEL

Benign

0.039

Sift

Benign

0.29

T;.;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.11

MutPred

0.15

Loss of disorder (P = 0.1539);.;Loss of disorder (P = 0.1539);

MVP

0.16

MPC

0.92

ClinPred

0.11

GERP RS

3.7

Varity_R

0.13

gMVP

0.21

Mutation Taster

=88/12

polymorphism

(source)

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

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17-44316493-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over