12-113927122-T-C

Position:

• chr12-113927122-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016196.4(RBM19):​c.2176A>G​(p.Ser726Gly) variant causes a missense 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. 16/21 in silico tools predict a benign 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: 0.623

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]

RBM19 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038112193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM19	NM_016196.4	c.2176A>G	p.Ser726Gly	missense_variant	17/24	ENST00000261741.10	NP_057280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM19	ENST00000261741.10	c.2176A>G	p.Ser726Gly	missense_variant	17/24	1	NM_016196.4	ENSP00000261741.5
RBM19	ENST00000392561.7	c.2176A>G	p.Ser726Gly	missense_variant	17/25	1		ENSP00000376344.3
RBM19	ENST00000545145.6	c.2176A>G	p.Ser726Gly	missense_variant	17/25	2		ENSP00000442053.2
RBM19	ENST00000552386.1	n.310A>G		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Jan 04, 2024

The c.2176A>G (p.S726G) alteration is located in exon 17 (coding exon 17) of the RBM19 gene. This alteration results from a A to G substitution at nucleotide position 2176, causing the serine (S) at amino acid position 726 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.60	.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.070
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.090
MutPred		0.23		Loss of phosphorylation at S726 (P = 0.0035);Loss of phosphorylation at S726 (P = 0.0035);Loss of phosphorylation at S726 (P = 0.0035);
MVP		0.66
MPC		0.11
ClinPred		0.12	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.16

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: rs776391021; hg19: chr12-114364927;