NM_001134363.3:c.2727_2741delGACAGTGGACGAGGT

Variant names:

• chr10-110821342-TGGTGACAGTGGACGA-T
• rs876657979
• NM_001134363.3:c.2727_2741delGACAGTGGACGAGGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP3

The NM_001134363.3(RBM20):​c.2727_2741delGACAGTGGACGAGGT​(p.Thr910_Val914del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 22 uncertain in NM_001134363.3
• PM4: Nonframeshift variant in NON repetitive region in NM_001134363.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.2727_2741delGACAGTGGACGAGGT	p.Thr910_Val914del	disruptive_inframe_deletion	Exon 11 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.2562_2576delGACAGTGGACGAGGT	p.Thr855_Val859del	disruptive_inframe_deletion	Exon 11 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.2343_2357delGACAGTGGACGAGGT	p.Thr782_Val786del	disruptive_inframe_deletion	Exon 11 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.2343_2357delGACAGTGGACGAGGT	p.Thr782_Val786del	disruptive_inframe_deletion	Exon 11 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.2727_2741delGACAGTGGACGAGGT	p.Thr910_Val914del	disruptive_inframe_deletion	Exon 11 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.2727_2741delGACAGTGGACGAGGT	p.Thr910_Val914del	disruptive_inframe_deletion	Exon 11 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 14, 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.Thr910_Val914del variant in RBM20 has not been previously reported in indi viduals with cardiomyopathy. Data from large population studies is insufficient to assess its frequency. This variant is a deletion of 5 amino acids at positio n 910-914 in exon 11. It is unclear if this deletion will impact protein functio n. In summary, the clinical significance of the p.Thr910_Val914del variant is un certain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

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

Other links and lift over

dbSNP: rs876657979; hg19: chr10-112581100;