rs867232627

Positions:

• chr10-110835943-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000369519.4(RBM20):​c.3649G>A​(p.Gly1217Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,400,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RBM20 ENST00000369519.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.67

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.

• BP6: Variant 10-110835943-G-A is Benign according to our data. Variant chr10-110835943-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470615.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000216 (27/1248068) while in subpopulation EAS AF= 0.000694 (24/34584). AF 95% confidence interval is 0.000478. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 18. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3649G>A	p.Gly1217Arg	missense_variant	14/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3484G>A	p.Gly1162Arg	missense_variant	14/14		XP_016871592.1
RBM20	XM_017016104.3	c.3265G>A	p.Gly1089Arg	missense_variant	14/14		XP_016871593.1
RBM20	XM_047425116.1	c.3265G>A	p.Gly1089Arg	missense_variant	14/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3649G>A	p.Gly1217Arg	missense_variant	14/14	1	NM_001134363.3	ENSP00000358532	P1
RBM20	ENST00000465774.2	n.590G>A		non_coding_transcript_exon_variant	2/2	4
RBM20	ENST00000480343.2	n.282G>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000216 AC: 27 AN: 1248068 Hom.: 0 Cov.: 18 AF XY: 0.0000225 AC XY: 14 AN XY: 622608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000694

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000212

Gnomad4 OTH exome AF: 0.0000189

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74508

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 12, 2022	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The p.G1217R variant (also known as c.3649G>A), located in coding exon 14 of the RBM20 gene, results from a G to A substitution at nucleotide position 3649. The glycine at codon 1217 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.57
MutPred		0.20		Gain of MoRF binding (P = 0.013);
MVP		0.77
ClinPred		0.97	D
GERP RS		5.0
gMVP		0.48

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: rs867232627; hg19: chr10-112595701;