chr10-110812700-C-T

Variant names:

• chr10-110812700-C-T
• rs1417635
• NM_001134363.3:c.2303C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134363.3(RBM20):​c.2303C>T​(p.Ser768Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,551,660 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/8 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. S768W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (4 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.958
• Publications: 30 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=0.007951826).
• BP6: Variant 10-110812700-C-T is Benign according to our data. Variant chr10-110812700-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00535 (814/152236) while in subpopulation AFR AF = 0.0178 (738/41536). AF 95% confidence interval is 0.0167. There are 4 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 814 AD gene.

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.2303C>T	p.Ser768Leu	missense	Exon 9 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.2303C>T	p.Ser768Leu	missense	Exon 9 of 14	ENSP00000358532.3	Q5T481
	RBM20	ENST00000961386.1		c.2333C>T	p.Ser778Leu	missense	Exon 9 of 14	ENSP00000631445.1
	RBM20	ENST00000718239.1		c.2303C>T	p.Ser768Leu	missense	Exon 9 of 14	ENSP00000520684.1	Q5T481

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152118 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000769 AC: 1076 AN: 1399424 Hom.: 4 Cov.: 32 AF XY: 0.000697 AC XY: 481 AN XY: 690226

African (AFR) AF: 0.0181 AC: 571 AN: 31598

American (AMR) AF: 0.00134 AC: 48 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25182

East Asian (EAS) AF: 0.0000839 AC: 3 AN: 35738

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79226

European-Finnish (FIN) AF: 0.000203 AC: 10 AN: 49286

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5698

European-Non Finnish (NFE) AF: 0.000343 AC: 370 AN: 1078982

Other (OTH) AF: 0.00107 AC: 62 AN: 58010

GnomAD4 genome AF: 0.00535 AC: 814 AN: 152236 Hom.: 4 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74436

African (AFR) AF: 0.0178 AC: 738 AN: 41536

American (AMR) AF: 0.00301 AC: 46 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00812 Hom.: 65

Bravo AF: 0.00629

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Dilated cardiomyopathy 1DD (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.9
MetaRNN	Benign	0.0080	T
PhyloP100		0.96
Sift4G	Benign	0.33	T
Vest4		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1417635; hg19: chr10-112572458;