rs542392971

Variant names:

• chr10-110823603-G-A
• rs542392971
• NM_001134363.3:c.3440G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110823603-G-A
• chr10-110823603-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134363.3(RBM20):​c.3440G>A​(p.Ser1147Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S1147T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25421485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.3440G>A	p.Ser1147Asn	missense_variant	Exon 12 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.3275G>A	p.Ser1092Asn	missense_variant	Exon 12 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.3056G>A	p.Ser1019Asn	missense_variant	Exon 12 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.3056G>A	p.Ser1019Asn	missense_variant	Exon 12 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.3440G>A	p.Ser1147Asn	missense_variant	Exon 12 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.3440G>A	p.Ser1147Asn	missense_variant	Exon 12 of 14			ENSP00000520684.1
RBM20	ENST00000471172.1	n.16G>A		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 06, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.54	T
PhyloP100		5.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.31
Sift	Benign	0.099	T
Sift4G	Uncertain	0.0040	D
Vest4		0.24
MutPred		0.37		Gain of catalytic residue at S1147 (P = 0.0023);
MVP		0.61
ClinPred		0.74	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.52
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs542392971; hg19: chr10-112583361;