Genetic Variant RBM18:p.Glu125Asp (chr9-122245294-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033117.4(RBM18):c.375G>C(p.Glu125Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,822 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RBM18
NM_033117.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.886

Variant links:

Genes affected

RBM18 (HGNC:28413): (RNA binding motif protein 18) Predicted to enable RNA binding activity. Located in cytosol; intercellular bridge; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RBM18 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25417382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM18	NM_033117.4 link	c.375G>C	p.Glu125Asp	missense_variant	Exon 5 of 6	ENST00000417201.4	NP_149108.1	Q96H35
RBM18	NR_027125.2 link	n.517G>C		non_coding_transcript_exon_variant	Exon 5 of 7
RBM18	NR_027126.2 link	n.611G>C		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBM18	ENST00000417201.4 link	c.375G>C	p.Glu125Asp	missense_variant	Exon 5 of 6	1	NM_033117.4	ENSP00000409315.2	Q96H35
RBM18	ENST00000483428.1 link	n.565G>C		non_coding_transcript_exon_variant	Exon 6 of 7	1
RBM18	ENST00000491850.5 link	n.77G>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458822

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.375G>C (p.E125D) alteration is located in exon 5 (coding exon 4) of the RBM18 gene. This alteration results from a G to C substitution at nucleotide position 375, causing the glutamic acid (E) at amino acid position 125 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Benign

0.010

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.34

REVEL

Benign

0.15

Sift

Benign

0.42

Sift4G

Benign

0.62

Polyphen

0.96

Vest4

0.48

MutPred

0.16

Loss of glycosylation at S127 (P = 0.1234);

MVP

0.18

MPC

0.68

ClinPred

0.60

GERP RS

2.9

Varity_R

0.096

gMVP

0.32

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over