10-110835942-C-T

Position:

• chr10-110835942-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001134363.3(RBM20):​c.3648C>T​(p.Ser1216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,394,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: RBM20 NM_001134363.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-110835942-C-T is Benign according to our data. Variant chr10-110835942-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264328.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000328 (50/152350) while in subpopulation AMR AF= 0.00105 (16/15308). AF 95% confidence interval is 0.000655. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.3648C>T	p.Ser1216=	synonymous_variant	14/14	ENST00000369519.4
RBM20	XM_017016103.3	c.3483C>T	p.Ser1161=	synonymous_variant	14/14
RBM20	XM_017016104.3	c.3264C>T	p.Ser1088=	synonymous_variant	14/14
RBM20	XM_047425116.1	c.3264C>T	p.Ser1088=	synonymous_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.3648C>T	p.Ser1216=	synonymous_variant	14/14	1	NM_001134363.3	P1
RBM20	ENST00000465774.2	n.589C>T		non_coding_transcript_exon_variant	2/2	4
RBM20	ENST00000480343.2	n.281C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000238 AC: 34 AN: 143014 Hom.: 0 AF XY: 0.000210 AC XY: 16 AN XY: 76192

Gnomad AFR exome AF: 0.000526

Gnomad AMR exome AF: 0.000720

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.000792

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000551

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.0000676 AC: 84 AN: 1242162 Hom.: 0 Cov.: 18 AF XY: 0.0000629 AC XY: 39 AN XY: 619756

Gnomad4 AFR exome AF: 0.000430

Gnomad4 AMR exome AF: 0.000734

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000347

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000309

Gnomad4 OTH exome AF: 0.0000948

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74502

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000404

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	- -

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2022	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.49
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs554167951; hg19: chr10-112595700;