chr17-44313485-G-T

Variant names:

• chr17-44313485-G-T
• rs2047790213
• NM_001144825.2:c.440G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001144825.2(RUNDC3A):​c.440G>T​(p.Arg147Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,706 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. R147H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RUNDC3A NM_001144825.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.45
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNDC3A	NM_001144825.2	c.440G>T	p.Arg147Leu	missense_variant	Exon 4 of 11	ENST00000426726.8	NP_001138297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNDC3A	ENST00000426726.8	c.440G>T	p.Arg147Leu	missense_variant	Exon 4 of 11	1	NM_001144825.2	ENSP00000410862.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458706 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724940

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

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109422

Other (OTH) AF: 0.00 AC: 0 AN: 60216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	M;.;M
PhyloP100		9.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.7	D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.81
MutPred		0.51		Loss of MoRF binding (P = 0.0039);.;Loss of MoRF binding (P = 0.0039);
MVP		0.26
MPC		2.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.52
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2047790213; hg19: chr17-42390853;