rs1030751538

chr10-110799841-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001134363.3(RBM20):c.1723C>G(p.Gln575Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000715 in 1,399,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.64

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28331164).
• BP6: Variant 10-110799841-C-G is Benign according to our data. Variant chr10-110799841-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538036.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1723C>G	p.Gln575Glu	missense_variant	7/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1558C>G	p.Gln520Glu	missense_variant	7/14
RBM20	XM_017016104.3	c.1339C>G	p.Gln447Glu	missense_variant	7/14
RBM20	XM_047425116.1	c.1339C>G	p.Gln447Glu	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1723C>G	p.Gln575Glu	missense_variant	7/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 158010 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83354

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000325

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1399486 Hom.: 0 Cov.: 30 AF XY: 0.0000116 AC XY: 8 AN XY: 690250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000927

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The p.Q575E variant (also known as c.1723C>G), located in coding exon 7 of the RBM20 gene, results from a C to G substitution at nucleotide position 1723. The glutamine at codon 575 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.030	D
Vest4		0.42
MutPred		0.33		Loss of MoRF binding (P = 0.0598);
MVP		0.56
ClinPred		0.76	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1030751538; hg19: chr10-112559599;