chr10-110821650-G-A

Variant names:

• chr10-110821650-G-A
• rs727503391
• NM_001134363.3:c.3031G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001134363.3(RBM20):​c.3031G>A​(p.Ala1011Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,399,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 1 publications found

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]

RBM20 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1DD

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.098027974).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.3031G>A	p.Ala1011Thr	missense	Exon 11 of 14	NP_001127835.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.3031G>A	p.Ala1011Thr	missense	Exon 11 of 14	ENSP00000358532.3
	RBM20	ENST00000718239.1		c.3031G>A	p.Ala1011Thr	missense	Exon 11 of 14	ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1399440 Hom.: 0 Cov.: 33 AF XY: 0.0000116 AC XY: 8 AN XY: 690220

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1078974

Other (OTH) AF: 0.00 AC: 0 AN: 58010

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala1011Thr variant in RBM20 has not been reported in the literature or in la rge population studies. Alanine (Ala) at position 1011 is not conserved in mamma ls or evolutionarily distant species, and in fact, tree shrew has a Threonine (T hr) at this codon. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully ass ess the clinical significance of the Ala1011Thr variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.47	T
PhyloP100		2.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.21
Sift	Benign	0.19	T
Sift4G	Benign	0.29	T
Vest4		0.050
MutPred		0.12		Gain of phosphorylation at A1011 (P = 0.0051)
MVP		0.51
ClinPred		0.73	D
GERP RS		4.0
gMVP		0.089
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs727503391; hg19: chr10-112581408;