rs569846404

chr10-110781383-G-Achr10-110781383-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001134363.3(RBM20):c.774G>A(p.Ser258=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000883 in 1,551,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.90

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-110781383-G-A is Benign according to our data. Variant chr10-110781383-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 179494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110781383-G-A is described in Lovd as [Benign]. Variant chr10-110781383-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000112 (17/152304) while in subpopulation SAS AF= 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.774G>A	p.Ser258=	synonymous_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.609G>A	p.Ser203=	synonymous_variant	2/14
RBM20	XM_017016104.3	c.390G>A	p.Ser130=	synonymous_variant	2/14
RBM20	XM_047425116.1	c.390G>A	p.Ser130=	synonymous_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.774G>A	p.Ser258=	synonymous_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 19 AN: 153832 Hom.: 0 AF XY: 0.000135 AC XY: 11 AN XY: 81634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000703

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000858 AC: 120 AN: 1399320 Hom.: 0 Cov.: 32 AF XY: 0.0000913 AC XY: 63 AN XY: 690168

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000473

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000793

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 31, 2014	Ser258Ser in exon 2 of RBM20: This variant has not been previously reported in i ndividuals with cardiomyopathy or in large population studies. It is not expect ed to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. Ser258Ser in exon2 of RBM20 (allele frequency = n/a) -

Dilated cardiomyopathy 1DD Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2021

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.26
Dann	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs569846404; hg19: chr10-112541141;