rs542297252

Variant names:

• chr10-110831126-G-A
• rs542297252
• NM_001134363.3:c.3517G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001134363.3(RBM20):​c.3517G>A​(p.Glu1173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,551,588 control chromosomes in the GnomAD database, including 1 homozygotes. 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. E1173D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.60
• 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), G2P, Ambry Genetics
• familial isolated dilated cardiomyopathy

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000263 (4/152258) while in subpopulation SAS AF = 0.00083 (4/4820). AF 95% confidence interval is 0.000283. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 30 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	NM_001134363.3	MANE Select	c.3517G>A	p.Glu1173Lys	missense	Exon 13 of 14	NP_001127835.2	Q5T481

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.3517G>A	p.Glu1173Lys	missense	Exon 13 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.3547G>A	p.Glu1183Lys	missense	Exon 13 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.3517G>A	p.Glu1173Lys	missense	Exon 13 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152140 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: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000260 AC: 4 AN: 153930 AF XY: 0.0000367

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000214 AC: 30 AN: 1399330 Hom.: 1 Cov.: 30 AF XY: 0.0000304 AC XY: 21 AN XY: 690176

African (AFR) AF: 0.0000949 AC: 3 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

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

South Asian (SAS) AF: 0.000316 AC: 25 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49274

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078914

Other (OTH) AF: 0.0000345 AC: 2 AN: 57994

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000129 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Dilated cardiomyopathy 1DD (3)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.28	D
PhyloP100		9.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Vest4		0.82
MutPred		0.40		Gain of ubiquitination at E1173 (P = 0.0198)
MVP		0.85
ClinPred		0.58	D
GERP RS		5.4
gMVP		0.62
Mutation Taster		=65/35	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: rs542297252; hg19: chr10-112590884;