rs372923744

Positions:

• chr10-110812598-G-A
• chr10-110812598-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001134363.3(RBM20):​c.2201G>A​(p.Arg734Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,551,572 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R734W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.36

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18791142).
• BP6: Variant 10-110812598-G-A is Benign according to our data. Variant chr10-110812598-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00023 (35/152188) while in subpopulation AFR AF= 0.00082 (34/41458). AF 95% confidence interval is 0.000603. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2201G>A	p.Arg734Gln	missense_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2036G>A	p.Arg679Gln	missense_variant	9/14
RBM20	XM_017016104.3	c.1817G>A	p.Arg606Gln	missense_variant	9/14
RBM20	XM_047425116.1	c.1817G>A	p.Arg606Gln	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2201G>A	p.Arg734Gln	missense_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000769 AC: 12 AN: 156036 Hom.: 0 AF XY: 0.0000846 AC XY: 7 AN XY: 82734

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000436 AC: 61 AN: 1399384 Hom.: 0 Cov.: 32 AF XY: 0.0000507 AC XY: 35 AN XY: 690202

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74362

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000202 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2019

The p.Arg734Gln variant in RBM20 is classified as likely benign because it has been identified in 0.1% (19/16596) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2020

This variant is associated with the following publications: (PMID: 32880476) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

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	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Vest4		0.57
MVP		0.86
ClinPred		0.22	T
GERP RS		5.9
gMVP		0.47

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: rs372923744; hg19: chr10-112572356;