12-110515135-A-G

Position:

• chr12-110515135-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000409300.6(RAD9B):​c.574A>G​(p.Ser192Gly) variant causes a missense change. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAD9B ENST00000409300.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD9B	NM_001286535.2	c.574A>G	p.Ser192Gly	missense_variant	6/11	ENST00000409300.6	NP_001273464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD9B	ENST00000409300.6	c.574A>G	p.Ser192Gly	missense_variant	6/11	1	NM_001286535.2	ENSP00000386434	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1390480 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 686866

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jun 22, 2023

The c.574A>G (p.S192G) alteration is located in exon 6 (coding exon 6) of the RAD9B gene. This alteration results from a A to G substitution at nucleotide position 574, causing the serine (S) at amino acid position 192 to be replaced by a glycine (G). 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	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	.;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.68
MVP		0.73
MPC		0.15
ClinPred		0.98	D
GERP RS		5.5
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-110952940;