rs397516597

Variant names:

• chr10-110810464-T-TGAG
• rs397516597
• NM_001134363.3:c.1880+4_1880+6dupAGG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001134363.3(RBM20):​c.1880+4_1880+6dupAGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,550,344 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (8 hom.)
• Consequence: RBM20 NM_001134363.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 1.92
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 10-110810464-T-TGAG is Benign according to our data. Variant chr10-110810464-T-TGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43978.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00128 (194/152144) while in subpopulation NFE AF = 0.00235 (160/68028). AF 95% confidence interval is 0.00205. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 194 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.1880+4_1880+6dupAGG		splice_region intron	N/A	NP_001127835.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM20	ENST00000369519.4	TSL:1 MANE Select	c.1880+2_1880+3insGAG		splice_region intron	N/A	ENSP00000358532.3
	RBM20	ENST00000961386.1		c.1910+2_1910+3insGAG		splice_region intron	N/A	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.1880+2_1880+3insGAG		splice_region intron	N/A	ENSP00000520684.1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00106 AC: 166 AN: 156316 AF XY: 0.00111

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00286 AC: 3994 AN: 1398200 Hom.: 8 Cov.: 29 AF XY: 0.00280 AC XY: 1930 AN XY: 689672

African (AFR) AF: 0.000285 AC: 9 AN: 31582

American (AMR) AF: 0.000112 AC: 4 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79210

European-Finnish (FIN) AF: 0.000386 AC: 19 AN: 49234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00349 AC: 3762 AN: 1077974

Other (OTH) AF: 0.00343 AC: 199 AN: 57936

GnomAD4 genome AF: 0.00128 AC: 194 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74304

African (AFR) AF: 0.000628 AC: 26 AN: 41420

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68028

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.00140

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	1	1	Dilated cardiomyopathy 1DD (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516597; hg19: chr10-112570222;