rs371951525

Positions:

• chr10-110821506-A-G

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.2887A>G​(p.Lys963Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,551,892 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).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.365

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=0.018989593).
• BP6: Variant 10-110821506-A-G is Benign according to our data. Variant chr10-110821506-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165046.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr10-110821506-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152238) while in subpopulation NFE AF= 0.000529 (36/68036). AF 95% confidence interval is 0.000392. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.2887A>G	p.Lys963Glu	missense_variant	11/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.2722A>G	p.Lys908Glu	missense_variant	11/14		XP_016871592.1
RBM20	XM_017016104.3	c.2503A>G	p.Lys835Glu	missense_variant	11/14		XP_016871593.1
RBM20	XM_047425116.1	c.2503A>G	p.Lys835Glu	missense_variant	11/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.2887A>G	p.Lys963Glu	missense_variant	11/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000336 AC: 53 AN: 157640 Hom.: 0 AF XY: 0.000396 AC XY: 33 AN XY: 83276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.000588

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000709

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000500 AC: 700 AN: 1399654 Hom.: 0 Cov.: 33 AF XY: 0.000490 AC XY: 338 AN XY: 690322

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000278

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.000590

Gnomad4 OTH exome AF: 0.000517

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74374

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000194 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	The RBM20 c.2887A>G;p.Lys963Glu variant (rs371951525), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 165046). This variant is found in the non-Finnish European population with an allele frequency of 0.06% (43/76,676 alleles) in the Genome Aggregation Database. The lysine at codon 963 is moderately conserved, but computational analyses (SIFT:damaging, PolyPhen-2:benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Lys963Glu variant is uncertain at this time. Gene statement: Pathogenic variants in RBM20 are associated with autosomal dominant dilated cardiomyopathy 1DD (MIM: 613172). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2017

The p.Lys963Glu variant in RBM20 has been reported in 4 individuals with HCM, 1 with HCM and SCD, 1 with neonatal DCM, 1 with ARVC, and 1 with DCM who also carr ied a likely pathogenic variant in a different gene (Lopes 2015, LMM data). This variant has also been identified in 42/73470 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs371951 525) and has been reported in ClinVar (Variation ID: 165046) as of uncertain sig nificance. Please note that for diseases with clinical variability, reduced pene trance, or recessive inheritance, pathogenic variants may be present at a low fr equency in the general population. Lysine (Lys) at position 963 is not conserved in mammals and evolutionarily distant species, and 4 mammals (rabbit, alpaca, c amel, and tenrec) carry a glutamic acid (Glu) at this position, raising the poss ibility that this change may be tolerated. In summary, the clinical significance of the p.Lys963Glu variant is uncertain. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 16, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2021

This variant is associated with the following publications: (PMID: 25351510) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 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	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.50
DANN	Benign	0.95
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.30	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.32	T
Vest4		0.077
MVP		0.19
ClinPred		0.017	T
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.13

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: rs371951525; hg19: chr10-112581264;