rs369747752

chr10-110821524-G-Achr10-110821524-G-Cchr10-110821524-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134363.3(RBM20):c.2905G>A(p.Val969Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,552,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict 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. V969L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: -1.72

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029341966).
• BP6: Variant 10-110821524-G-A is Benign according to our data. Variant chr10-110821524-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}. Variant chr10-110821524-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000141 (197/1399668) while in subpopulation SAS AF= 0.000353 (28/79236). AF 95% confidence interval is 0.00025. There are 0 homozygotes in gnomad4_exome. There are 112 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2905G>A	p.Val969Ile	missense_variant	11/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2740G>A	p.Val914Ile	missense_variant	11/14
RBM20	XM_017016104.3	c.2521G>A	p.Val841Ile	missense_variant	11/14
RBM20	XM_047425116.1	c.2521G>A	p.Val841Ile	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2905G>A	p.Val969Ile	missense_variant	11/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000114 AC: 18 AN: 157576 Hom.: 0 AF XY: 0.000120 AC XY: 10 AN XY: 83230

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000817

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000141 AC: 197 AN: 1399668 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 112 AN XY: 690324

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74494

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0000772 AC: 2

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Jan 15, 2022	This missense variant resulted in an amino acid substitution of valine with isoleucine at codon 969 of the RBM20 gene. The variant has occurred in GnomAD with a total MAF of 0.0118% and with the highest MAF of 0.0438% in the South Asian population. This position is not conserved. In silico functional algorithm predicted with Polyphen calling it benign, and SIFT tolerated, but no functional studies were performed to confirm this prediction. This variant NM_001134363.3(RBM20):c.2905G>A (p.Val969Ile) is present in the ClinVar database (ID: 470606). The variant has not occurred in the literature in the association with the disease. Considering that this is a rare variant, whose impact on protein and association with the disease are unknown, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -

RBM20-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 08, 2022

The RBM20 c.2905G>A variant is predicted to result in the amino acid substitution p.Val969Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-112581282-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2023

Identified in association with HCM in published literature (Lopes et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510) -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 06, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

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	Benign	0.066
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.0030
Dann	Benign	0.49
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.018	N
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	0.46	T
Vest4		0.037
MVP		0.072
ClinPred		0.011	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
gMVP		0.053

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: rs369747752; hg19: chr10-112581282;