rs397516625

chr10-110781534-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.925G>A(p.Gly309Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,551,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 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. G309E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 2.70

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09436169).
• BP6: Variant 10-110781534-G-A is Benign according to our data. Variant chr10-110781534-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44030.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000184 (28/152298) while in subpopulation AMR AF= 0.00177 (27/15296). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.925G>A	p.Gly309Arg	missense_variant	2/14	ENST00000369519.4
RBM20	XM_017016103.3	c.760G>A	p.Gly254Arg	missense_variant	2/14
RBM20	XM_017016104.3	c.541G>A	p.Gly181Arg	missense_variant	2/14
RBM20	XM_047425116.1	c.541G>A	p.Gly181Arg	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.925G>A	p.Gly309Arg	missense_variant	2/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000778 AC: 12 AN: 154264 Hom.: 0 AF XY: 0.0000855 AC XY: 7 AN XY: 81908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 24 AN: 1399342 Hom.: 0 Cov.: 32 AF XY: 0.0000174 AC XY: 12 AN XY: 690182

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.0000862

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 27, 2024	The p.Gly309Arg variant in RBM20 is classified as likely benign because it has been identified in 0.07% (36/51000) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2014	p.Gly309Arg (GGG>AGG): c.925 G>A in exon 2 of the RBM20 gene (NM_001134363.1). The G309R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G309R variant was not observed in approximately 2000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G309R 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. However, 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. Missense mutations in nearby residues have not been reported in association with cardiomyopathy, indicating this region of the protein may tolerate change.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 DCM-CRDM panel(s). -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 24, 2019

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Sep 05, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2021

The c.925G>A (p.G309R) alteration is located in exon 2 (coding exon 2) of the RBM20 gene. This alteration results from a G to A substitution at nucleotide position 925, causing the glycine (G) at amino acid position 309 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.74	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Vest4		0.33
MutPred		0.16		Loss of glycosylation at S306 (P = 0.0519);
MVP		0.51
ClinPred		0.24	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.53

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: rs397516625; hg19: chr10-112541292;