rs183007628

chr10-110797583-G-Achr10-110797583-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001134363.3(RBM20):c.1603G>A(p.Val535Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000574 in 1,551,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V535L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.99

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27874976).
• BP6: Variant 10-110797583-G-A is Benign according to our data. Variant chr10-110797583-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202044.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000302 (46/152234) while in subpopulation AMR AF= 0.00268 (41/15286). AF 95% confidence interval is 0.00203. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1603G>A	p.Val535Ile	missense_variant	6/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1438G>A	p.Val480Ile	missense_variant	6/14
RBM20	XM_017016104.3	c.1219G>A	p.Val407Ile	missense_variant	6/14
RBM20	XM_047425116.1	c.1219G>A	p.Val407Ile	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1603G>A	p.Val535Ile	missense_variant	6/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.0000318 AC: 5 AN: 157294 Hom.: 0 AF XY: 0.0000240 AC XY: 2 AN XY: 83176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000307 AC: 43 AN: 1399442 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 18 AN XY: 690232

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.000190

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74426

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000570

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2023

The p.V535I variant (also known as c.1603G>A), located in coding exon 6 of the RBM20 gene, results from a G to A substitution at nucleotide position 1603. The valine at codon 535 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in a patient with dilated cardiomyopathy (DCM) who also carried an alteration in LDB3, and was also detected in association with DCM in an additional cohort; however, details were limited (Li D et al, Clin Transl Sci 2010 Jun; 3(3):90-7; Smith E et al. J Am Heart Assoc. 2022 May;11(9):e024501). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2020

Reported in one individual with DCM; however, this individual also harbored a variant in the LDB3 gene, and there were not a sufficient number of affected family members to assess segregation with disease (Li et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 202044; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22466703, 20590677, 30547036, 29304022) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.41
Sift	Benign	0.040	D
Sift4G	Benign	0.070	T
Vest4		0.75
MVP		0.82
ClinPred		0.36	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.46

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: rs183007628; hg19: chr10-112557341;