12-110506641-A-G

Position:

• chr12-110506641-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001286533.2(RAD9B):​c.-295A>G variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAD9B NM_001286533.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.05

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]

RAD9B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110506641-A-G is Pathogenic according to our data. Variant chr12-110506641-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 694314.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33851856). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD9B	NM_001286535.2	c.336A>G	p.Ile112Met	missense_variant	4/11	ENST00000409300.6	NP_001273464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD9B	ENST00000409300.6	c.336A>G	p.Ile112Met	missense_variant	4/11	1	NM_001286535.2	ENSP00000386434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453668 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723552

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: 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	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.63	.;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.056	T;D;D;T;T
Sift4G	Benign	0.097	T;D;D;T;T
Polyphen		0.78, 0.98	.;.;P;.;D
Vest4		0.44
MVP		0.48
MPC		0.036
ClinPred		0.97	D
GERP RS		1.5
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1593037878; hg19: chr12-110944446;