chr10-110812355-C-T

Variant names:

• chr10-110812355-C-T
• rs727505310
• NM_001134363.3:c.1958C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP6 BS1 BS2

The NM_001134363.3(RBM20):​c.1958C>T​(p.Thr653Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,551,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T653T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.26

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

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a region_of_interest RS (size 27) in uniprot entity RBM20_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_001134363.3
• BP6: Variant 10-110812355-C-T is Benign according to our data. Variant chr10-110812355-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180045.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr10-110812355-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000125 (19/152218) while in subpopulation NFE AF = 0.000147 (10/68038). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1958C>T	p.Thr653Ile	missense_variant	Exon 9 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1793C>T	p.Thr598Ile	missense_variant	Exon 9 of 14		XP_016871592.1
RBM20	XM_017016104.3	c.1574C>T	p.Thr525Ile	missense_variant	Exon 9 of 14		XP_016871593.1
RBM20	XM_047425116.1	c.1574C>T	p.Thr525Ile	missense_variant	Exon 9 of 14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1958C>T	p.Thr653Ile	missense_variant	Exon 9 of 14	1	NM_001134363.3	ENSP00000358532.3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000148 AC: 23 AN: 155066 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000658

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000456

GnomAD4 exome AF: 0.000141 AC: 197 AN: 1399312 Hom.: 0 Cov.: 32 AF XY: 0.000141 AC XY: 97 AN XY: 690168

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31598

Gnomad4 AMR exome AF: 0.0000280 AC: 1 AN: 35704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25182

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35738

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 79236

Gnomad4 FIN exome AF: 0.00130 AC: 64 AN: 49158

Gnomad4 NFE exome AF: 0.000110 AC: 119 AN: 1078974

Gnomad4 Remaining exome AF: 0.000224 AC: 13 AN: 58022

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74352

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000753 AC: 0.00075287 AN: 0.00075287

Gnomad4 NFE AF: 0.000147 AC: 0.000146977 AN: 0.000146977

Gnomad4 OTH AF: 0.000478 AC: 0.000478011 AN: 0.000478011

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000110 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1DD Uncertain:1 Benign:1

Jun 09, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 19, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr653Ile variant in RBM20 has been identified by our laboratory in 1 Cauc asian individual with HCM, and has also been identified in 3/6614 European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ). Computational prediction tools and conservation analysis suggest that the p.T hr653Ile variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Thr653Ile variant is uncertain. -

not provided Uncertain:1

Nov 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with DCM and an individual with HCM, however, additional patient-specific data were not described (Gigli et al., 2019; van Lint et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 31514951, 32917565, 34823266, 35893073, HolmstromL2022[Preprint]) -

Cardiovascular phenotype Benign:1

May 16, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.13	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.73
MVP		0.82
ClinPred		0.47	T
GERP RS		5.4
gMVP		0.54
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs727505310; hg19: chr10-112572113;