9-107321986-A-C

Variant names:

• chr9-107321986-A-C
• NM_002874.5:c.685A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002874.5(RAD23B):​c.685A>C​(p.Ile229Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD23B NM_002874.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33

Genes affected

RAD23B (HGNC:9813): (RAD23 homolog B, nucleotide excision repair protein) The protein encoded by this gene is one of two human homologs of Saccharomyces cerevisiae Rad23, a protein involved in the nucleotide excision repair (NER). This protein was found to be a component of the protein complex that specifically complements the NER defect of xeroderma pigmentosum group C (XP-c) cell extracts in vitro. This protein was also shown to interact with, and elevate the nucleotide excision activity of 3-methyladenine-DNA glycosylase (MPG), which suggested a role in DNA damage recognition in base excision repair. This protein contains an N-terminal ubiquitin-like domain, which was reported to interact with 26S proteasome, and thus this protein may be involved in the ubiquitin mediated proteolytic pathway in cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37136006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD23B	NM_002874.5	c.685A>C	p.Ile229Leu	missense_variant	Exon 7 of 10	ENST00000358015.8	NP_002865.1
RAD23B	NM_001244713.1	c.622A>C	p.Ile208Leu	missense_variant	Exon 7 of 10		NP_001231642.1
RAD23B	NM_001244724.2	c.469A>C	p.Ile157Leu	missense_variant	Exon 7 of 10		NP_001231653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD23B	ENST00000358015.8	c.685A>C	p.Ile229Leu	missense_variant	Exon 7 of 10	1	NM_002874.5	ENSP00000350708.3
RAD23B	ENST00000416373.6	c.469A>C	p.Ile157Leu	missense_variant	Exon 7 of 10	1		ENSP00000405623.2
RAD23B	ENST00000457811.1	c.288+3107A>C		intron_variant	Intron 3 of 3	3		ENSP00000396975.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685A>C (p.I229L) alteration is located in exon 7 (coding exon 7) of the RAD23B gene. This alteration results from a A to C substitution at nucleotide position 685, causing the isoleucine (I) at amino acid position 229 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	0.053
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.55	P;.
Vest4		0.61
MutPred		0.41		Gain of disorder (P = 0.0724);.;
MVP		0.65
MPC		0.71
ClinPred		0.84	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-110084267;