Genetic Variant NM_014059.3:c.47C>A (chr13-41457754-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014059.3(RGCC):c.47C>A(p.Ala16Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000804 in 1,243,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A16V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

RGCC
NM_014059.3 missense, splice_region

Scores

Splicing: ADA: 0.006811

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.836

Publications

0 publications found

Variant links:

Genes affected

RGCC (HGNC:20369): (regulator of cell cycle) This gene is thought to regulate cell cycle progression. It is induced by p53 in response to DNA damage, or by sublytic levels of complement system proteins that result in activation of the cell cycle. The encoded protein localizes to the cytoplasm during interphase and to centrosomes during mitosis. The protein forms a complex with polo-like kinase 1. The protein also translocates to the nucleus in response to treatment with complement system proteins, and can associate with and increase the kinase activity of cell division cycle 2 protein. In different assays and cell types, overexpression of this protein has been shown to activate or suppress cell cycle progression. [provided by RefSeq, Jul 2008]

RGCC links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33117223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014059.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGCC	NM_014059.3	MANE Select	c.47C>A	p.Ala16Glu	missense splice_region	Exon 1 of 5	NP_054778.2	Q9H4X1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGCC	ENST00000379359.4	TSL:1 MANE Select	c.47C>A	p.Ala16Glu	missense splice_region	Exon 1 of 5	ENSP00000368664.3	Q9H4X1-1
RGCC	ENST00000888696.1		c.47C>A	p.Ala16Glu	missense	Exon 1 of 5	ENSP00000558755.1
RGCC	ENST00000888694.1		c.47C>A	p.Ala16Glu	missense splice_region	Exon 1 of 5	ENSP00000558753.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.04e-7

AC:

AN:

1243356

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

607894

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:

23798

American (AMR)

AF:

0.00

AC:

AN:

10586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16824

East Asian (EAS)

AF:

0.00

AC:

AN:

27810

South Asian (SAS)

AF:

0.00

AC:

AN:

53916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4516

European-Non Finnish (NFE)

AF:

9.89e-7

AC:

AN:

1011626

Other (OTH)

AF:

0.00

AC:

AN:

50650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.031

Eigen

Benign

0.14

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.1

PhyloP100

0.84

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.090

REVEL

Benign

0.20

Sift

Benign

0.070

Sift4G

Benign

0.28

Polyphen

0.99

Vest4

0.31

MutPred

0.27

Gain of solvent accessibility (P = 0.005)

MVP

0.32

MPC

0.76

ClinPred

0.33

GERP RS

2.9

PromoterAI

0.21

Neutral

(source)

Varity_R

0.25

gMVP

0.20

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0068

dbscSNV1_RF

Benign

0.096

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over