NM_001134363.3:c.1614G>T

Variant names:

• chr10-110797594-G-T
• NM_001134363.3:c.1614G>T
• RBM20 p.Leu538Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP7

The NM_001134363.3(RBM20):c.1614G>T (p.Leu538Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.74
• 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 -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (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).
	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.1614G>T p.Leu538Leu	synonymous	Exon 6 of 14	Prot: NP_001127835.2 UniProt:

RBM20 NM_001134363.3

MANE Select

HGVSc / HGVSpc.1614G>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.1614G>T p.Leu538Leu	synonymous	Exon 6 of 14	Prot: ENSP00000358532.3 UniProt:
	RBM20 ENST00000961386.1		c.1644G>T p.Leu548Leu	synonymous	Exon 6 of 14	Prot: ENSP00000631445.1 UniProt:
	RBM20 ENST00000718239.1		c.1614G>T p.Leu538Leu	synonymous	Exon 6 of 14	Prot: ENSP00000520684.1 UniProt:

RBM20 ENST00000369519.4

TSL:1MANE Select

HGVSc / HGVSpc.1614G>Tp.Leu538Leu

Exon rankExon 6 of 14

synonymous

Prot: ENSP00000358532.3UniProt: Q5T481

RBM20 ENST00000961386.1

HGVSc / HGVSpc.1644G>Tp.Leu548Leu

Exon rankExon 6 of 14

synonymous

Prot: ENSP00000631445.1UniProt: A0ACI8V4S1

RBM20 ENST00000718239.1

HGVSc / HGVSpc.1614G>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:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.9
DANN	Benign	0.80
GPN-Star LLR	N/A	-3.8
GPN-Star score	N/A	3.8
PhyloP100	Benign	2.7
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 9 of 9 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

hg19: chr10-112557352;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar