rs183130427

Positions:

• chr10-110781139-C-G
• chr10-110781139-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134363.3(RBM20):​c.530C>G​(p.Thr177Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,551,606 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T177I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.73

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1491827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.530C>G	p.Thr177Arg	missense_variant	2/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.365C>G	p.Thr122Arg	missense_variant	2/14		XP_016871592.1
RBM20	XM_017016104.3	c.146C>G	p.Thr49Arg	missense_variant	2/14		XP_016871593.1
RBM20	XM_047425116.1	c.146C>G	p.Thr49Arg	missense_variant	2/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.530C>G	p.Thr177Arg	missense_variant	2/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399394 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690196

Gnomad4 AFR exome AF: 0.0000633

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

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: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2021	Variant summary: RBM20 c.530C>G (p.Thr177Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 156040 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.530C>G has been reported in the literature in individual(s) affected with Cardiomyopathy (Parikh_2019). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 22, 2013	Variant classified as Uncertain Significance - Favor Benign. The Thr177Arg varia nt in RBM20 has not been reported in the literature, but has been identified by our laboratory in one child with HCM. Coverage at this position from the NHLBI E xome Sequencing Project (http://evs.gs.washington.edu/EVS/) was insufficient to determine the frequency of this variant in large European American and African A merican populations. Threonine (Thr) at position 117 is not conserved in mammals and additional computational analyses (biochemical amino acid properties, Align GVGD, and PolyPhen2) suggest that this variant may not impact the protein, thoug h this information is not predictive enough to rule out pathogenicity. Finally, another variant at this position (Thr177Ile) has been identified in an African p opulation by the 1000 Genomes project, raising the possibility that changes at t his position may be tolerated. Although this data supports that the Thr177Arg va riant may be benign, additional studies are needed to fully assess its clinical significance. -

Dilated cardiomyopathy 1DD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2017

In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Not Scored"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). While this variant is not present in population databases (rs183130427), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a RBM20-related disease. ClinVar contains an entry for this variant (Variation ID: 44023). This sequence change replaces threonine with arginine at codon 177 of the RBM20 protein (p.Thr177Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.43	N
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.55	T
Vest4		0.18
MutPred		0.22		Loss of glycosylation at T177 (P = 0.0033);
MVP		0.53
ClinPred		0.62	D
GERP RS		4.6
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs183130427; hg19: chr10-112540897;