Genetic Variant RCC1:p.Asn149Ser (chr1-28535054-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001381865.2(RCC1):c.446A>G(p.Asn149Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RCC1
NM_001381865.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.17

Publications

0 publications found

Variant links:

Genes affected

RCC1 (HGNC:1913): (regulator of chromosome condensation 1) Enables several functions, including guanyl-nucleotide exchange factor activity; nucleosomal DNA binding activity; and protein heterodimerization activity. Involved in several processes, including G1/S transition of mitotic cell cycle; regulation of mitotic nuclear division; and spindle organization. Located in chromatin; cytoplasm; and nucleus. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

RCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCC1	NM_001381865.2 link	c.446A>G	p.Asn149Ser	missense_variant	Exon 8 of 13	ENST00000683442.1	NP_001368794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCC1	ENST00000683442.1 link	c.446A>G	p.Asn149Ser	missense_variant	Exon 8 of 13		NM_001381865.2	ENSP00000508074.1		P18754-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111764

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.539A>G (p.N180S) alteration is located in exon 6 (coding exon 5) of the RCC1 gene. This alteration results from a A to G substitution at nucleotide position 539, causing the asparagine (N) at amino acid position 180 to be replaced by a serine (S). 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

0.084

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.22

T;.;T;.;T;T;T;.;.;T

Eigen

Benign

0.015

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;D;D;.;D;.;D;D;D

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.57

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.3

L;.;.;.;L;.;L;.;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.48

N;.;N;.;N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.67

T;.;T;.;T;T;T;T;T;T

Sift4G

Benign

1.0

T;.;T;.;T;T;T;T;T;T

Polyphen

0.56

P;B;.;.;P;.;P;B;.;.

Vest4

0.51

MutPred

0.74

Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;.;Gain of sheet (P = 0.1208);

MVP

0.82

MPC

0.34

ClinPred

0.82

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.42

gMVP

0.74

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.40

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr1-28535054-A-G

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