rs199868951

Positions:

• chr10-110781057-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000369519.4(RBM20):​c.448G>A​(p.Ala150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,551,758 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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 0.00053 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (5 hom.)
• Consequence: RBM20 ENST00000369519.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: -0.316

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004958421).
• BP6: Variant 10-110781057-G-A is Benign according to our data. Variant chr10-110781057-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44018.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=2}. Variant chr10-110781057-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.448G>A	p.Ala150Thr	missense_variant	2/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.283G>A	p.Ala95Thr	missense_variant	2/14		XP_016871592.1
RBM20	XM_017016104.3	c.64G>A	p.Ala22Thr	missense_variant	2/14		XP_016871593.1
RBM20	XM_047425116.1	c.64G>A	p.Ala22Thr	missense_variant	2/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.448G>A	p.Ala150Thr	missense_variant	2/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152178 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00123 AC: 193 AN: 157176 Hom.: 1 AF XY: 0.00112 AC XY: 93 AN XY: 83146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00226

GnomAD4 exome AF: 0.000469 AC: 657 AN: 1399580 Hom.: 5 Cov.: 32 AF XY: 0.000453 AC XY: 313 AN XY: 690280

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.0186

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000936

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152178 Hom.: 2 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74340

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.000514

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000943 AC: 3

ExAC AF: 0.00189 AC: 51

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 11, 2012	Ala150Thr in exon 2 of RBM20: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 14 mammals have a Threonine (Thr; this variant) at this position despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelihood of impact to the protein. In addition, this variant has been identified in 3/3182 European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS). -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 26, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala150Thr (c.448 G>A, A150T) in the RBM20 gene The variant has not been reported in association with disease. In silico analysis with PolyPhen-2 predicts the variant to be benign. The alanine at codon 150 is not conserved across species, and is in fact a threonine in some species, including mammals. Mutation taster predicts the variant to be benign. In total the variant has not been seen in 5 of ~2,579 published controls and individuals from publicly available population datasets. The variant is reported online in 3 of 1591 Caucasian individuals and 1 of 692 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 27th, 2013). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is listed in dbSNP (rs199868951), which refers to the NHLBI data and data from ClinSeq. In ClinSeq it was observed in 1 of 296 individuals; this cohort approximates a general population sample (with respect to Mendelian disease). It is listed in 1000 genomes but only in reference to the dbSNP entry (as of January 27th, 2013). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2022	Variant summary: RBM20 c.448G>A (p.Ala150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 157176 control chromosomes in the gnomAD database, including one homozygote. The observed variant frequency is approximately 26 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 23, 2021

- -

RBM20-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial dilated cardiomyopathy and peripheral neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 03, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

RBM20: BP4, BS1 -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2016

This alteration is classified as 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	0.063
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.079
DANN	Benign	0.48
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.091	N
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.15
Sift	Benign	0.43	T
Sift4G	Benign	0.19	T
Vest4		0.092
MVP		0.088
ClinPred		0.018	T
GERP RS		-6.5
gMVP		0.20

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: rs199868951; hg19: chr10-112540815; COSMIC: COSV65705680;