rs7908490

Variant names:

• chr10-110781126-C-A
• rs7908490
• NM_001134363.3:c.517C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110781126-C-A
• chr10-110781126-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134363.3(RBM20):​c.517C>A​(p.Pro173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,551,686 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P173S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.265
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001773119).
• BP6: Variant 10-110781126-C-A is Benign according to our data. Variant chr10-110781126-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

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.517C>A	p.Pro173Thr	missense	Exon 2 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.517C>A	p.Pro173Thr	missense	Exon 2 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.517C>A	p.Pro173Thr	missense	Exon 2 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.517C>A	p.Pro173Thr	missense	Exon 2 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3399 AN: 152118 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00504 AC: 789 AN: 156518 AF XY: 0.00379

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00227 AC: 3179 AN: 1399450 Hom.: 112 Cov.: 32 AF XY: 0.00195 AC XY: 1345 AN XY: 690236

African (AFR) AF: 0.0775 AC: 2448 AN: 31598

American (AMR) AF: 0.00538 AC: 192 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: 0.000215 AC: 17 AN: 79236

European-Finnish (FIN) AF: 0.0000406 AC: 2 AN: 49266

Middle Eastern (MID) AF: 0.00351 AC: 20 AN: 5698

European-Non Finnish (NFE) AF: 0.000174 AC: 188 AN: 1078994

Other (OTH) AF: 0.00538 AC: 312 AN: 58034

GnomAD4 genome AF: 0.0224 AC: 3403 AN: 152236 Hom.: 124 Cov.: 32 AF XY: 0.0210 AC XY: 1566 AN XY: 74428

African (AFR) AF: 0.0774 AC: 3212 AN: 41520

American (AMR) AF: 0.00941 AC: 144 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67996

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00815 Hom.: 80

Bravo AF: 0.0257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0708 AC: 98

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00648 AC: 177

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Dilated cardiomyopathy 1DD (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.21	N
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.27
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.65	T
Vest4		0.071
MVP		0.25
ClinPred		0.0045	T
GERP RS		1.5
gMVP		0.25
Mutation Taster		=98/2	polymorphism (auto)

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: rs7908490; hg19: chr10-112540884;