10-110812700-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134363.3(RBM20):c.2303C>G(p.Ser768Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,551,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S768L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.958

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026998222).
• BP6: Variant 10-110812700-C-G is Benign according to our data. Variant chr10-110812700-C-G is described in ClinVar as [Benign]. Clinvar id is 238547.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 = 0.00275 (418/152242) while in subpopulation AFR AF= 0.00939 (390/41542). AF 95% confidence interval is 0.00862. There are 2 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 415 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.2303C>G	p.Ser768Trp	missense_variant	9/14	ENST00000369519.4
RBM20	XM_017016103.3	c.2138C>G	p.Ser713Trp	missense_variant	9/14
RBM20	XM_017016104.3	c.1919C>G	p.Ser640Trp	missense_variant	9/14
RBM20	XM_047425116.1	c.1919C>G	p.Ser640Trp	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.2303C>G	p.Ser768Trp	missense_variant	9/14	1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152124 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00932

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000263 AC: 368 AN: 1399424 Hom.: 0 Cov.: 32 AF XY: 0.000235 AC XY: 162 AN XY: 690226

Gnomad4 AFR exome AF: 0.00864

Gnomad4 AMR exome AF: 0.000756

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000232

Gnomad4 OTH exome AF: 0.000690

GnomAD4 genome AF: 0.00275 AC: 418 AN: 152242 Hom.: 2 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74442

Gnomad4 AFR AF: 0.00939

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00560 Hom.: 65

Bravo AF: 0.00316

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 12, 2019

- -

Dilated cardiomyopathy 1DD Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Benign	-0.96
Cadd	Benign	17
MetaRNN	Benign	0.027	T
Sift4G	Uncertain	0.011	D
Vest4		0.40
gMVP		0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1417635; hg19: chr10-112572458;