12-113924720-A-T

Variant names:

• chr12-113924720-A-T
• NM_016196.4:c.2282T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016196.4(RBM19):​c.2282T>A​(p.Ile761Asn) 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: 33)
• Consequence: RBM19 NM_016196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

Genes affected

RBM19 (HGNC:29098): (RNA binding motif protein 19) This gene encodes a nucleolar protein that contains six RNA-binding motifs. The encoded protein may be involved in regulating ribosome biogenesis. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM19	NM_016196.4	c.2282T>A	p.Ile761Asn	missense_variant	Exon 18 of 24	ENST00000261741.10	NP_057280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM19	ENST00000261741.10	c.2282T>A	p.Ile761Asn	missense_variant	Exon 18 of 24	1	NM_016196.4	ENSP00000261741.5
RBM19	ENST00000392561.7	c.2282T>A	p.Ile761Asn	missense_variant	Exon 18 of 25	1		ENSP00000376344.3
RBM19	ENST00000545145.6	c.2282T>A	p.Ile761Asn	missense_variant	Exon 18 of 25	2		ENSP00000442053.2
RBM19	ENST00000552386.1	n.416T>A		non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2282T>A (p.I761N) alteration is located in exon 18 (coding exon 18) of the RBM19 gene. This alteration results from a T to A substitution at nucleotide position 2282, causing the isoleucine (I) at amino acid position 761 to be replaced by an asparagine (N). 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
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	4.1	H;H;H
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.70		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.45
MPC		0.78
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-114362525;