NM_001134363.3:c.27G>C

Variant names:

• chr10-110644481-G-C
• rs1157177960
• NM_001134363.3:c.27G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001134363.3(RBM20):​c.27G>C​(p.Gln9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,368,230 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.41
• 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, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3048493).
• BP6: Variant 10-110644481-G-C is Benign according to our data. Variant chr10-110644481-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 957630.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.27G>C	p.Gln9His	missense_variant	Exon 1 of 14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.26+1041G>C		intron_variant	Intron 1 of 13		XP_016871592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.27G>C	p.Gln9His	missense_variant	Exon 1 of 14	1	NM_001134363.3	ENSP00000358532.3
RBM20	ENST00000718239.1	c.27G>C	p.Gln9His	missense_variant	Exon 1 of 14			ENSP00000520684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000869 AC: 1 AN: 115016 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1368230 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 674912

African (AFR) AF: 0.00 AC: 0 AN: 28270

American (AMR) AF: 0.00 AC: 0 AN: 33452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24318

East Asian (EAS) AF: 0.0000607 AC: 2 AN: 32926

South Asian (SAS) AF: 0.00 AC: 0 AN: 76670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070330

Other (OTH) AF: 0.00 AC: 0 AN: 56778

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

May 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q9H variant (also known as c.27G>C), located in coding exon 1 of the RBM20 gene, results from a G to C substitution at nucleotide position 27. The glutamine at codon 9 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1DD Benign:1

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	0.085
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.35	N
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.26	T
PhyloP100		1.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Vest4		0.25
MutPred		0.15		Gain of glycosylation at S8 (P = 0.1014);
MVP		0.69
ClinPred		0.90	D
GERP RS		2.3
PromoterAI		0.0021	Neutral
gMVP		0.32
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1157177960; hg19: chr10-112404239;