12-110505723-A-C

Position:

• chr12-110505723-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286535.2(RAD9B):​c.224A>C​(p.Glu75Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD9B NM_001286535.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.963

Genes affected

RAD9B (HGNC:21700): (RAD9 checkpoint clamp component B) Predicted to be involved in DNA integrity checkpoint signaling; DNA repair; and cellular response to ionizing radiation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062663585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD9B	NM_001286535.2	c.224A>C	p.Glu75Ala	missense_variant	3/11	ENST00000409300.6	NP_001273464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD9B	ENST00000409300.6	c.224A>C	p.Glu75Ala	missense_variant	3/11	1	NM_001286535.2	ENSP00000386434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jul 19, 2023

The c.224A>C (p.E75A) alteration is located in exon 3 (coding exon 3) of the RAD9B gene. This alteration results from a A to C substitution at nucleotide position 224, causing the glutamic acid (E) at amino acid position 75 to be replaced by an alanine (A). 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
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.015	.;.;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.58	.;T;T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.063	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N;N;N;N;N
REVEL	Benign	0.032
Sift	Pathogenic	0.0	D;T;T;D;T
Sift4G	Benign	0.091	T;T;T;T;T
Polyphen		0.046, 0.021	.;.;B;.;B
Vest4		0.13
MVP		0.14
MPC		0.023
ClinPred		0.21	T
GERP RS		2.7
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr12-110943528;