rs397516598

Positions:

• chr10-110812370-C-G
• chr10-110812370-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_001134363.3(RBM20):​c.1973C>G​(p.Ser658Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,551,584 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).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.57

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3938089).
• BP6: Variant 10-110812370-C-G is Benign according to our data. Variant chr10-110812370-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43982.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1973C>G	p.Ser658Cys	missense_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.1808C>G	p.Ser603Cys	missense_variant	9/14
RBM20	XM_017016104.3	c.1589C>G	p.Ser530Cys	missense_variant	9/14
RBM20	XM_047425116.1	c.1589C>G	p.Ser530Cys	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1973C>G	p.Ser658Cys	missense_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000645 AC: 1 AN: 154990 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 24 AN: 1399348 Hom.: 0 Cov.: 32 AF XY: 0.0000130 AC XY: 9 AN XY: 690180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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: 0.0000213

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2013

The Ser658Cys variant in RBM20 has not been reported in the literature. It has b een identified by our laboratory in 1 Caucasian individual with DCM (LMM unpubli shed data), though it did not segregate with disease in an affected family membe r. The frequency of this variant in large European American and African American populations cannot be determined from the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/) because coverage at this position was insufficient or unavailable. Serine (Ser) at position 658 is not conserved in mammals, thoug h additional computational analyses (biochemical amino acid properties, AlignGVG D, and SIFT) do not provide strong support for or against an impact to the prote in. Finally, this variant lies within exon 9, which encodes a conserved protein domain where other pathogenic variants have been reported (Brauch 2009, Li 2010) . In summary, additional studies are needed to fully assess the clinical signifi cance of the Ser658Cys variant. -

Primary familial dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Dilated cardiomyopathy 1DD Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	0.71	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.042	D
Vest4		0.37
MutPred		0.20		Loss of phosphorylation at S658 (P = 0.0116);
MVP		0.65
ClinPred		0.87	D
GERP RS		3.9
gMVP		0.50

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: rs397516598; hg19: chr10-112572128;