rs397516597

Positions:

• chr10-110810464-T-TGAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001134363.3(RBM20):​c.1880+4_1880+6dup variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,550,344 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (8 hom.)
• Consequence: RBM20 NM_001134363.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 1.92

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 10-110810464-T-TGAG is Benign according to our data. Variant chr10-110810464-T-TGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43978.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (194/152144) while in subpopulation NFE AF= 0.00235 (160/68028). AF 95% confidence interval is 0.00205. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1880+4_1880+6dup		splice_region_variant, intron_variant		ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1715+4_1715+6dup		splice_region_variant, intron_variant			XP_016871592.1
RBM20	XM_017016104.3	c.1496+4_1496+6dup		splice_region_variant, intron_variant			XP_016871593.1
RBM20	XM_047425116.1	c.1496+4_1496+6dup		splice_region_variant, intron_variant			XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1880+4_1880+6dup		splice_region_variant, intron_variant		1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00106 AC: 166 AN: 156316 Hom.: 1 AF XY: 0.00111 AC XY: 92 AN XY: 82832

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00286 AC: 3994 AN: 1398200 Hom.: 8 Cov.: 29 AF XY: 0.00280 AC XY: 1930 AN XY: 689672

Gnomad4 AFR exome AF: 0.000285

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.000386

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00128 AC: 194 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74304

Gnomad4 AFR AF: 0.000628

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.00140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2021	Variant summary: RBM20 c.1880+4_1880+6dupAGG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 156316 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.1880+4_1880+6dupAGG has been reported in the literature in sequencing studies reporting individuals affected with sporadic or familial Dialated Cardiomyopathy (example, Haas_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=1; likely benign, n=3, benign, n=1). One submitter reports this variant as having co-occurred with another pathogenic variant that clearly explained the patient phenotype. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 10, 2020	The c.1880+4_1880+6dupAGG variant in RBM20 is classified as likely benign because it has been identified in 0.2% (177/75818) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	This variant is associated with the following publications: (PMID: 25163546) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RBM20: BP4, BS1, BS2 -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	RBM20 NM_001134363.2 exon 8 c.1880+4_1880+6dup: This variant has been reported in the literature in at least one individual with DCM (Haas 2015 PMID:25163546). However, this variant is also present in 0.2% (177/75818) of European alleles in the Genome Aggregation Database, including 2 homozygotes (https://gnomad.broadinstitute.org/variant/10-112570222-T-TGAG) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:43978). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant occurs in the splice region, computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 22, 2019

- -

Primary familial hypertrophic cardiomyopathy Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 21, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516597; hg19: chr10-112570222;