chr10-110810372-G-C

Position:

• chr10-110810372-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000369519.4(RBM20):​c.1801-11G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,549,418 control chromosomes in the GnomAD database, including 876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (82 hom., cov: 32)
  • Exomes 𝑓: 0.027 (794 hom.)
• Consequence: RBM20 ENST00000369519.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003465
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.296

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 10-110810372-G-C is Benign according to our data. Variant chr10-110810372-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 43977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110810372-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1801-11G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1636-11G>C		splice_polypyrimidine_tract_variant, intron_variant			XP_016871592.1
RBM20	XM_017016104.3	c.1417-11G>C		splice_polypyrimidine_tract_variant, intron_variant			XP_016871593.1
RBM20	XM_047425116.1	c.1417-11G>C		splice_polypyrimidine_tract_variant, intron_variant			XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1801-11G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4033 AN: 152150 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.0995

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0350

GnomAD3 exomes AF: 0.0350 AC: 5478 AN: 156494 Hom.: 156 AF XY: 0.0388 AC XY: 3216 AN XY: 82944

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.0288

Gnomad SAS exome AF: 0.0942

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0314

GnomAD4 exome AF: 0.0270 AC: 37697 AN: 1397150 Hom.: 794 Cov.: 30 AF XY: 0.0291 AC XY: 20034 AN XY: 689216

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.0246

Gnomad4 SAS exome AF: 0.0941

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0265 AC: 4042 AN: 152268 Hom.: 82 Cov.: 32 AF XY: 0.0282 AC XY: 2103 AN XY: 74460

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.0266

Gnomad4 SAS AF: 0.0998

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0151 Hom.: 9

Bravo AF: 0.0243

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	1801-11G>C in intron 7 of RBM20: This variant is not expected to have clinical s ignificance because it has been identified in 2.6% (67/2532) of European America n chromosomes and 3.3% (23/702) of African American chromosomes from a broad pop ulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/ ; dbSNP rs12572941) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dilated cardiomyopathy 1DD Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.024
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

Publications

LitVar

Other links and lift over

dbSNP: rs12572941; hg19: chr10-112570130;