dbSNP rs371736071: RUNDC3A:p.Arg72Ser (chr17-44312686-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001144825.2(RUNDC3A):c.214C>A(p.Arg72Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R72H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RUNDC3A
NM_001144825.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.24

Publications

1 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:

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

RUNDC3A-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNDC3A	NM_001144825.2 link	c.214C>A	p.Arg72Ser	missense_variant	Exon 2 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.214C>A	p.Arg72Ser	missense_variant	Exon 2 of 11	1	NM_001144825.2	ENSP00000410862.2		Q59EK9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1405764

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32234

American (AMR)

AF:

0.00

AC:

AN:

37464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24540

East Asian (EAS)

AF:

0.0000539

AC:

AN:

37118

South Asian (SAS)

AF:

0.00

AC:

AN:

78528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5094

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082372

Other (OTH)

AF:

0.00

AC:

AN:

58338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.008463), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

M;M;M

PhyloP100

3.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

N;.;N

REVEL

Uncertain

0.44

Sift

Benign

0.50

T;.;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.90

MutPred

0.77

Loss of stability (P = 0.0974);Loss of stability (P = 0.0974);Loss of stability (P = 0.0974);

MVP

0.27

MPC

2.3

ClinPred

0.99

GERP RS

3.1

Varity_R

0.46

gMVP

0.83

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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rs371736071

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over