10-110821695-G-T

Position:

• chr10-110821695-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001134363.3(RBM20):​c.3076G>T​(p.Glu1026*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

Genes affected

RBM20 (HGNC:27424): (RNA binding motif protein 20) This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3076G>T	p.Glu1026*	stop_gained	11/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.2911G>T	p.Glu971*	stop_gained	11/14		XP_016871592.1
RBM20	XM_017016104.3	c.2692G>T	p.Glu898*	stop_gained	11/14		XP_016871593.1
RBM20	XM_047425116.1	c.2692G>T	p.Glu898*	stop_gained	11/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3076G>T	p.Glu1026*	stop_gained	11/14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Benign	0.75	D
Vest4		0.74
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs866975469; hg19: chr10-112581453;