chr1-28529880-G-A

Position:

• chr1-28529880-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001381865.2(RCC1):​c.14G>A​(p.Arg5His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RCC1 NM_001381865.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24559823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCC1	NM_001381865.2	c.14G>A	p.Arg5His	missense_variant	5/13	ENST00000683442.1	NP_001368794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCC1	ENST00000683442.1	c.14G>A	p.Arg5His	missense_variant	5/13		NM_001381865.2	ENSP00000508074.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461776 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.14G>A (p.R5H) alteration is located in exon 2 (coding exon 1) of the RCC1 gene. This alteration results from a G to A substitution at nucleotide position 14, causing the arginine (R) at amino acid position 5 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;T;.;T;T;T;.;.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;.;T;T;.;T;.;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.81	L;L;.;.;L;.;L;L;.;.;.
MutationTaster	Benign	0.84	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D;.;D;.;D;D;D;N;N;.;D
REVEL	Benign	0.13
Sift	Benign	0.049	D;.;D;.;D;D;D;T;D;.;D
Sift4G	Uncertain	0.013	D;.;D;.;D;D;D;D;D;D;D
Polyphen		0.91	P;D;.;.;P;.;P;D;.;.;.
Vest4		0.53
MutPred		0.34		Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);.;Loss of MoRF binding (P = 0.0825);
MVP		0.54
MPC		1.4
ClinPred		0.93	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs745907798; hg19: chr1-28856392; COSMIC: COSV100868057; COSMIC: COSV100868057;