1-28532189-A-G

Variant names:

• chr1-28532189-A-G
• NM_001381865.2:c.280A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001381865.2(RCC1):​c.280A>G​(p.Asn94Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RCC1 NM_001381865.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 1-28532189-A-G is Pathogenic according to our data. Variant chr1-28532189-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2687492.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCC1	NM_001381865.2	c.280A>G	p.Asn94Asp	missense_variant	Exon 7 of 13	ENST00000683442.1	NP_001368794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCC1	ENST00000683442.1	c.280A>G	p.Asn94Asp	missense_variant	Exon 7 of 13		NM_001381865.2	ENSP00000508074.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

See cases Pathogenic:1

Jan 11, 2024

Newman Lab, University of Manchester

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This is a novel disease-gene association -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;D;.;D;D;D;.;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;.;D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;.;M;.;.;.
PhyloP100		9.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D;.;D;.;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D;.;D;.;D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;.;D;.;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;D;.;D;D;.;.
Vest4		0.90
MutPred		0.94		Gain of disorder (P = 0.0621);.;Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);.;.;Gain of disorder (P = 0.0621);
MVP		0.97
MPC		1.3
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.95
Mutation Taster		=9/91	disease causing

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

Other links and lift over

hg19: chr1-28858701;