rs61735272

Variant names:

• chr10-110783376-T-C
• rs61735272
• NM_001134363.3:c.1286T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001134363.3(RBM20):​c.1286T>C​(p.Leu429Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,551,300 control chromosomes in the GnomAD database, including 6 homozygotes. 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 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:15
• Conservation: PhyloP100: 4.99
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04264185).
• BP6: Variant 10-110783376-T-C is Benign according to our data. Variant chr10-110783376-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43969.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00122 (186/152362) while in subpopulation NFE AF = 0.0021 (143/68032). AF 95% confidence interval is 0.00182. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 186 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.1286T>C	p.Leu429Pro	missense	Exon 3 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.1286T>C	p.Leu429Pro	missense	Exon 3 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.1286T>C	p.Leu429Pro	missense	Exon 3 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.1286T>C	p.Leu429Pro	missense	Exon 3 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000955 AC: 151 AN: 158180 AF XY: 0.000899

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000884

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.00207 AC: 2901 AN: 1398938 Hom.: 5 Cov.: 30 AF XY: 0.00203 AC XY: 1398 AN XY: 689984

African (AFR) AF: 0.000317 AC: 10 AN: 31558

American (AMR) AF: 0.000616 AC: 22 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79194

European-Finnish (FIN) AF: 0.000851 AC: 42 AN: 49376

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5546

European-Non Finnish (NFE) AF: 0.00250 AC: 2694 AN: 1078620

Other (OTH) AF: 0.00215 AC: 125 AN: 58056

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74506

African (AFR) AF: 0.000553 AC: 23 AN: 41584

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00130

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00409 AC: 13

ExAC AF: 0.000902 AC: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	3	2	Dilated cardiomyopathy 1DD (5)
-	-	5	not specified (5)
-	1	1	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.086
Sift	Benign	0.036	D
Sift4G	Benign	0.068	T
Vest4		0.68
MVP		0.52
ClinPred		0.11	T
GERP RS		4.4
gMVP		0.85
Mutation Taster		=59/41	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: rs61735272; hg19: chr10-112543134;