RBM20 p.Leu538Leu

Variant names:

• chr10-110797592-C-T
• rs876657569
• NM_001134363.3:c.1612C>T
• RBM20 p.Leu538Leu

Your query was ambiguous. Multiple possible variants found:

• chr10-110797592-C-T
• chr10-110797594-G-A
• chr10-110797594-G-C
• chr10-110797594-G-T
• chr10-110797592-CTG-TTA

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_StrongBP7

The NM_001134363.3(RBM20):c.1612C>T (p.Leu538Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000129 (AC=2) in the gnomAD database across 1,551,710 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000657. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.66
• 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, PanelApp Australia, G2P
• familial isolated dilated cardiomyopathy

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

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000657 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001134363.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RBM20 NM_001134363.3	MANE Select	c.1612C>T p.Leu538Leu	synonymous	Exon 6 of 14	Prot: NP_001127835.2 UniProt:

RBM20 NM_001134363.3

MANE Select

HGVSc / HGVSpc.1612C>Tp.Leu538Leu

Exon rankExon 6 of 14

synonymous

Prot: NP_001127835.2UniProt: Q5T481

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RBM20 ENST00000369519.4	TSL:1MANE Select	c.1612C>T p.Leu538Leu	synonymous	Exon 6 of 14	Prot: ENSP00000358532.3 UniProt:
	RBM20 ENST00000961386.1		c.1642C>T p.Leu548Leu	synonymous	Exon 6 of 14	Prot: ENSP00000631445.1 UniProt:
	RBM20 ENST00000718239.1		c.1612C>T p.Leu538Leu	synonymous	Exon 6 of 14	Prot: ENSP00000520684.1 UniProt:

RBM20 ENST00000369519.4

TSL:1MANE Select

HGVSc / HGVSpc.1612C>Tp.Leu538Leu

Exon rankExon 6 of 14

synonymous

Prot: ENSP00000358532.3UniProt: Q5T481

RBM20 ENST00000961386.1

HGVSc / HGVSpc.1642C>Tp.Leu548Leu

Exon rankExon 6 of 14

synonymous

Prot: ENSP00000631445.1UniProt: A0ACI8V4S1

RBM20 ENST00000718239.1

HGVSc / HGVSpc.1612C>Tp.Leu538Leu

Exon rankExon 6 of 14

synonymous

Prot: ENSP00000520684.1UniProt: Q5T481

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152120	Cov:32
GnomAD4 exome	AF: 7.15e-7	AC:1	Hom:0	AN:1399472	Cov:30
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152238	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48442	0.0000134	1	74534

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated cardiomyopathy 1DD (1)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.78
GPN-Star LLR	N/A	-2.3
GPN-Star score	N/A	2.3
PhyloP100	Benign	2.7

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs876657569;

hg19: chr10-112557350;

COSMIC: COSV65704552;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar