Genetic Variant RBM41:p.Arg415Gln (chrX-107067597-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001324242.2(RBM41):c.1244G>A(p.Arg415Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000993 in 1,208,743 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00010 ( 0 hom. 41 hem. )

Consequence

RBM41
NM_001324242.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.16

Variant links:

Genes affected

RBM41 (HGNC:25617): (RNA binding motif protein 41) Predicted to enable U12 snRNA binding activity and pre-mRNA intronic binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Predicted to be part of U12-type spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

RBM41 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023754746).

BP6

Variant X-107067597-C-T is Benign according to our data. Variant chrX-107067597-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2524048.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-107067597-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM41	NM_001324242.2 link	c.1244G>A	p.Arg415Gln	missense_variant	Exon 8 of 8	ENST00000685964.1	NP_001311171.1	A0A8I5KYC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM41	ENST00000685964.1 link	c.1244G>A	p.Arg415Gln	missense_variant	Exon 8 of 8		NM_001324242.2	ENSP00000509650.1		A0A8I5KYC8

Frequencies

GnomAD3 genomes

AF:

0.0000897

AC:

AN:

111506

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33752

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000492

AC:

AN:

182916

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

67534

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000100

AC:

110

AN:

1097237

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

362803

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:

0.0000371

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000897

AC:

AN:

111506

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33752

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000375

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 01, 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

Benign

0.056

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0010

DANN

Benign

0.67

DEOGEN2

Benign

0.12

.;T

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.040

Sift

Benign

0.85

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.0

.;B

Vest4

0.067

MVP

0.33

MPC

0.19

ClinPred

0.040

GERP RS

-11

Varity_R

0.033

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over