rs1265727354

Variant names:

• chr10-110784340-G-C
• NM_001134363.3:c.1338-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-110784340-G-C
• chr10-110784340-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001134363.3(RBM20):​c.1338-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000143 in 1,397,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024972856 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of -30, new splice context is: tctttgtttaacttattaAGgag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1338-1G>C		splice_acceptor_variant, intron_variant	Intron 3 of 13	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1173-1G>C		splice_acceptor_variant, intron_variant	Intron 3 of 13		XP_016871592.1
RBM20	XM_017016104.3	c.954-1G>C		splice_acceptor_variant, intron_variant	Intron 3 of 13		XP_016871593.1
RBM20	XM_047425116.1	c.954-1G>C		splice_acceptor_variant, intron_variant	Intron 3 of 13		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1338-1G>C		splice_acceptor_variant, intron_variant	Intron 3 of 13	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689542

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.66		Position offset: 1

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: chr10-112544098;