rs876657977

Variant names:

• chr10-110812577-CAGA-C
• rs876657977
• NM_001134363.3:c.2183_2185delAAG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BS1_Supporting BS2

The NM_001134363.3(RBM20):​c.2183_2185delAAG​(p.Glu728del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000715 in 1,399,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: RBM20 NM_001134363.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.53
• Publications: 2 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 -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001134363.3. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000715 (10/1399394) while in subpopulation MID AF = 0.000351 (2/5698). AF 95% confidence interval is 0.0000616. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.2183_2185delAAG	p.Glu728del	disruptive_inframe_deletion	Exon 9 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.2018_2020delAAG	p.Glu673del	disruptive_inframe_deletion	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1799_1801delAAG	p.Glu600del	disruptive_inframe_deletion	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1799_1801delAAG	p.Glu600del	disruptive_inframe_deletion	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.2183_2185delAAG	p.Glu728del	disruptive_inframe_deletion	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.2183_2185delAAG	p.Glu728del	disruptive_inframe_deletion	Exon 9 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000192 AC: 3 AN: 155862 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1399394 Hom.: 0 AF XY: 0.00000724 AC XY: 5 AN XY: 690208

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49258

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078974

Other (OTH) AF: 0.0000172 AC: 1 AN: 58006

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu728del variant in RBM20 has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to asse ss the frequency of this variant. This variant causes an in-frame deletion of 1 amino acid residue at position 728. It is unclear if this deletion will impact t he protein. In summary, the clinical significance of the p.Glu728del variant is uncertain. -

Dilated cardiomyopathy 1DD Uncertain:1

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2183_2185del, results in the deletion of 1 amino acid(s) of the RBM20 protein (p.Glu728del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 37652022). ClinVar contains an entry for this variant (Variation ID: 229191). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Mar 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2183_2185delAAG variant (also known as p.E728del) is located in coding exon 9 of the RBM20 gene. This variant results from an in-frame AAG deletion at nucleotide positions 2183 to 2185. This results in the in-frame deletion of a glutamic acid at codon 728. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been reported in association with dilated cardiomyopathy (DCM) (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). The deleted amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5
Mutation Taster		=78/22	polymorphism

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: rs876657977; hg19: chr10-112572335;