rs397516593

chr10-110644576-T-TGCA

Variant summary

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

The NM_001134363.3(RBM20):c.128_130dup(p.Gln43dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00133 in 1,525,996 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (36 hom.)
• Consequence: RBM20 NM_001134363.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 3.99

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 10-110644576-T-TGCA is Benign according to our data. Variant chr10-110644576-T-TGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43970.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000894 (135/151004) while in subpopulation SAS AF= 0.0253 (120/4740). AF 95% confidence interval is 0.0216. There are 3 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.128_130dup	p.Gln43dup	inframe_insertion	1/14	ENST00000369519.4
RBM20	XM_017016103.3	c.26+1142_26+1144dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.128_130dup	p.Gln43dup	inframe_insertion	1/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 136 AN: 150884 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.00393 AC: 476 AN: 121236 Hom.: 9 AF XY: 0.00520 AC XY: 348 AN XY: 66978

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00138 AC: 1892 AN: 1374992 Hom.: 36 Cov.: 33 AF XY: 0.00197 AC XY: 1336 AN XY: 678152

Gnomad4 AFR exome AF: 0.000170

Gnomad4 AMR exome AF: 0.000176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.000894 AC: 135 AN: 151004 Hom.: 3 Cov.: 32 AF XY: 0.00141 AC XY: 104 AN XY: 73762

Gnomad4 AFR AF: 0.000292

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000433 Hom.: 0

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2015	p.Gln43_Pro44insGln in exon 1 of RBM20: This variant is not expected to have cli nical significance because it has been identified in 2.0% (133/6770) of South As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs397516593). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2022	- -

Cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2014	The c.128_130dupAGC variant in the RBM20 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. This in-frame duplication does not occur in any of the domains thought to be critical to protein structure/function including Proline-rich domains, Glutamine-rich domains, or in the RNA Recognition Motif (RRM). The NHLBI ESP Exome Variant Server reports c.128_130dupAGC was not observed in approximately 2000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, population data from ethnically-matched backgrounds was not available at the time of this report. With the clinical and molecular information available at this time, we cannot definitively determine if c.128_130dupAGC is a disease-causing mutation or a rare benign variant. The variant is found in DCM,DCM-CRDM panel(s). -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 20, 2017	- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated cardiomyopathy 1DD Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2017

This alteration is classified as 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: rs397516593; hg19: chr10-112404334;