12-113191465-C-G

Variant names:

• chr12-113191465-C-G
• rs780914706
• NM_032848.3:c.458C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032848.3(RITA1):​c.458C>G​(p.Ser153Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S153L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RITA1 NM_032848.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

Genes affected

RITA1 (HGNC:25925): (RBPJ interacting and tubulin associated 1) Enables tubulin binding activity. Involved in negative regulation of Notch signaling pathway and nuclear export. Located in centrosome; cytoplasm; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000257286 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33014947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RITA1	NM_032848.3	MANE Select	c.458C>G	p.Ser153Trp	missense	Exon 4 of 4	NP_116237.1	Q96K30-1
	RITA1	NM_001286215.2		c.530C>G	p.Ser177Trp	missense	Exon 3 of 3	NP_001273144.1	Q96K30-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RITA1	ENST00000548278.2	TSL:1 MANE Select	c.458C>G	p.Ser153Trp	missense	Exon 4 of 4	ENSP00000449841.1	Q96K30-1
	RITA1	ENST00000552495.1	TSL:2	c.530C>G	p.Ser177Trp	missense	Exon 3 of 3	ENSP00000448680.1	Q96K30-3
	RITA1	ENST00000549621.5	TSL:2	c.458C>G	p.Ser153Trp	missense	Exon 4 of 4	ENSP00000448289.1	Q96K30-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451916 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720372

African (AFR) AF: 0.0000300 AC: 1 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 85776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104814

Other (OTH) AF: 0.00 AC: 0 AN: 59808

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.2
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.18		Gain of catalytic residue at R155 (P = 0.0024)
MVP		0.24
MPC		0.92
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.34
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs780914706; hg19: chr12-113629270;