12-110518741-G-A

Position:

• chr12-110518741-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000409300.6(RAD9B):​c.661G>A​(p.Gly221Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD9B ENST00000409300.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.55

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
• PP5: Variant 12-110518741-G-A is Pathogenic according to our data. Variant chr12-110518741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 694312.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD9B	NM_001286535.2	c.661G>A	p.Gly221Arg	missense_variant	7/11	ENST00000409300.6	NP_001273464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD9B	ENST00000409300.6	c.661G>A	p.Gly221Arg	missense_variant	7/11	1	NM_001286535.2	ENSP00000386434	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250420 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458856 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725838

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neural tube defect Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Finnell Lab, Baylor College of Medicine

-

In vitro functional study described this variant affects RAD9B's protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.051	.;.;T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	.;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.042	D;T;T;D;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.97, 0.96	.;.;D;.;D
Vest4		0.57
MVP		0.61
MPC		0.068
ClinPred		0.98	D
GERP RS		4.6
gMVP		0.63

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: rs763079713; hg19: chr12-110956546;