10-110835948-C-A

Variant names:

• chr10-110835948-C-A
• rs1235947843
• NM_001134363.3:c.3654C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001134363.3(RBM20):​c.3654C>A​(p.Ile1218Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000824 in 1,213,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1218I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.313
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP7: Synonymous conserved (PhyloP=-0.313 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3654C>A	p.Ile1218Ile	synonymous_variant	Exon 14 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3489C>A	p.Ile1163Ile	synonymous_variant	Exon 14 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.3270C>A	p.Ile1090Ile	synonymous_variant	Exon 14 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.3270C>A	p.Ile1090Ile	synonymous_variant	Exon 14 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3654C>A	p.Ile1218Ile	synonymous_variant	Exon 14 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.3654C>A	p.Ile1218Ile	synonymous_variant	Exon 14 of 14			ENSP00000520684.1
RBM20	ENST00000465774.2	n.595C>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
RBM20	ENST00000480343.2	n.287C>A		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.24e-7 AC: 1 AN: 1213378 Hom.: 0 Cov.: 16 AF XY: 0.00000165 AC XY: 1 AN XY: 606396

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27210

American (AMR) AF: 0.00 AC: 0 AN: 33430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23684

East Asian (EAS) AF: 0.00 AC: 0 AN: 34350

South Asian (SAS) AF: 0.00 AC: 0 AN: 73954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 914692

Other (OTH) AF: 0.00 AC: 0 AN: 51692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.57
DANN	Benign	0.62
PhyloP100		-0.31

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

Other links and lift over

dbSNP: rs1235947843; hg19: chr10-112595706;