rs794729156

chr10-110821665-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001134363.3(RBM20):c.3046G>A(p.Gly1016Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,551,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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. G1016A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.58

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13349214).
• BP6: Variant 10-110821665-G-A is Benign according to our data. Variant chr10-110821665-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202073.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000143 (20/1399452) while in subpopulation AMR AF= 0.00056 (20/35704). AF 95% confidence interval is 0.000371. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.3046G>A	p.Gly1016Ser	missense_variant	11/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2881G>A	p.Gly961Ser	missense_variant	11/14
RBM20	XM_017016104.3	c.2662G>A	p.Gly888Ser	missense_variant	11/14
RBM20	XM_047425116.1	c.2662G>A	p.Gly888Ser	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.3046G>A	p.Gly1016Ser	missense_variant	11/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 18 AN: 156636 Hom.: 0 AF XY: 0.0000723 AC XY: 6 AN XY: 82980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000729

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1399452 Hom.: 0 Cov.: 33 AF XY: 0.0000101 AC XY: 7 AN XY: 690232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000560

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 29, 2017	p.Gly1016Ser (c.3046G>A) in exon 11 of the RBM20 gene (NM_001134363.2) Given that there are no cases reported in the literature with this variant and its relatively high frequency in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data available on this variant. This variant is present in ClinVar, and was submitted by a single lab: GeneDx classifies this variant as a variant of uncertain significance. This variant is located outside of a putative "hot spot" of pathogenic variation in RBM20 (the RS domain in exon 9). The variant was reported online in 18 of 75,679 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 18 of 11,978 individuals of Latino descent (MAF=0.075%). Additional variants at codon 1016 are present in gnomAD: p.Gly1016Asp is present in 4 out of 75,667 individuals and p.Gly1016Ala is present in 74 out of 11,410 individuals of South Asian descent (including in 1 homozygote). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2015	p.Gly1016Ser (GGC>AGC): c.3046 G>A in exon 11 of the RBM20 gene (NM_001134363.1). Mutations in the RBM20 gene have been reported in approximately 3% of of patients with DCM (Refaat M et al., 2011). The G1016S variant has not been published as a mutation or as a benign polymorphism to our knowledge. The G1016S variant was not observed in approximately 2,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the G1016S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function; however at least two models predict this variant predicts this variant likely does not alter the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with DCM. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The p.G1016S variant (also known as c.3046G>A), located in coding exon 11 of the RBM20 gene, results from a G to A substitution at nucleotide position 3046. The glycine at codon 1016 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Benign	0.16	T
Sift4G	Benign	0.39	T
Vest4		0.092
MutPred		0.14		Gain of phosphorylation at G1016 (P = 0.005);
MVP		0.74
ClinPred		0.15	T
GERP RS		4.1
gMVP		0.21

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: rs794729156; hg19: chr10-112581423;