rs558674954

chr10-110810389-G-A

Variant summary

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

The NM_001134363.3(RBM20):c.1807G>A(p.Gly603Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,551,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G603G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 8.70

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 10-110810389-G-A is Benign according to our data. Variant chr10-110810389-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263763.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000269 (41/152284) while in subpopulation AMR AF= 0.00163 (25/15296). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1807G>A	p.Gly603Arg	missense_variant	8/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1642G>A	p.Gly548Arg	missense_variant	8/14
RBM20	XM_017016104.3	c.1423G>A	p.Gly475Arg	missense_variant	8/14
RBM20	XM_047425116.1	c.1423G>A	p.Gly475Arg	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1807G>A	p.Gly603Arg	missense_variant	8/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000172 AC: 27 AN: 156524 Hom.: 0 AF XY: 0.000205 AC XY: 17 AN XY: 82956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000734

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000496

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.0000457 AC: 64 AN: 1398946 Hom.: 0 Cov.: 30 AF XY: 0.0000594 AC XY: 41 AN XY: 689994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000476

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000336

Gnomad4 SAS exome AF: 0.0000757

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000260

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74470

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000400 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2021

Reported in an abstract in a patient diagnosed with DCM who had aggressive disease progression requiring total artificial heart implantation at 34 years of age; expression studies using myocardial cells from this patient showed aberrant splicing of RBM20 target genes (Gartner-Rommel et al., 2018); Reported in an abstract in a patient diagnosed with DCM; however, the specific nucleotide substitution resulting in the G603R missense change was not provided and this individual also harbored additional cardiac variants, including a TTN nonsense variant (Gartner-Rommel et al., 2018); Reported in ClinVar (ClinVar Variant ID# 263763; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2020

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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.74	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.74
MutPred		0.44		Gain of MoRF binding (P = 0.0607);
MVP		0.70
ClinPred		0.30	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs558674954; hg19: chr10-112570147;