rs138436392

Variant names:

• chr10-110812275-C-A
• rs138436392
• NM_001134363.3:c.1881-3C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110812275-C-A
• chr10-110812275-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001134363.3(RBM20):​c.1881-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 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: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 splice_region, intron
• Scores: Splicing: ADA: 0.9784
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84
• Publications: 0 publications found

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]

RBM20 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1DD

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1881-3C>A		splice_region_variant, intron_variant	Intron 8 of 13	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1716-3C>A		splice_region_variant, intron_variant	Intron 8 of 13		XP_016871592.1
RBM20	XM_017016104.3	c.1497-3C>A		splice_region_variant, intron_variant	Intron 8 of 13		XP_016871593.1
RBM20	XM_047425116.1	c.1497-3C>A		splice_region_variant, intron_variant	Intron 8 of 13		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1881-3C>A		splice_region_variant, intron_variant	Intron 8 of 13	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.1881-3C>A		splice_region_variant, intron_variant	Intron 8 of 13			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385482 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 681362

African (AFR) AF: 0.00 AC: 0 AN: 31372

American (AMR) AF: 0.00 AC: 0 AN: 35112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24728

East Asian (EAS) AF: 0.00 AC: 0 AN: 35468

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070896

Other (OTH) AF: 0.00 AC: 0 AN: 57452

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.61
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138436392; hg19: chr10-112572033;