rs563762318

chr10-110831154-G-Achr10-110831154-G-C

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.3545G>A(p.Arg1182His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000928 in 1,551,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1182C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:4
• Conservation: PhyloP100: 9.60

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=0.0721263).
• BP6: Variant 10-110831154-G-A is Benign according to our data. Variant chr10-110831154-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180484.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000854 (13/152294) while in subpopulation EAS AF= 0.00193 (10/5184). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.3545G>A	p.Arg1182His	missense_variant	13/14	ENST00000369519.4
RBM20	XM_017016103.3	c.3380G>A	p.Arg1127His	missense_variant	13/14
RBM20	XM_017016104.3	c.3161G>A	p.Arg1054His	missense_variant	13/14
RBM20	XM_047425116.1	c.3161G>A	p.Arg1054His	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.3545G>A	p.Arg1182His	missense_variant	13/14	1	NM_001134363.3	P1
RBM20	ENST00000471172.1	n.121G>A		non_coding_transcript_exon_variant	2/2	5
RBM20	ENST00000480343.2	n.178G>A		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000279 AC: 43 AN: 153912 Hom.: 0 AF XY: 0.000220 AC XY: 18 AN XY: 81652

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00248

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.0000656

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000936 AC: 131 AN: 1399310 Hom.: 0 Cov.: 31 AF XY: 0.0000884 AC XY: 61 AN XY: 690156

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.0000250

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74476

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000181

ExAC AF: 0.000171 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	Jun 01, 2023	- -

Primary dilated cardiomyopathy Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Mar 13, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	Jun 01, 2023	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 19, 2015	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2020

This variant is associated with the following publications: (PMID: 31918855, 31514951, 30165862, 28416588, 26458567) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2021

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	0.28
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.072	T
MetaSVM	Uncertain	0.061	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.91
MVP		0.83
ClinPred		0.16	T
GERP RS		5.6
gMVP		0.57

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: rs563762318; hg19: chr10-112590912; COSMIC: COSV105300225; COSMIC: COSV105300225;