Genetic Variant RBM46:p.Asp159Gly (chr4-154798135-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_144979.5(RBM46):c.476A>G(p.Asp159Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,613,874 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 2 hom. )

Consequence

RBM46
NM_144979.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

RBM46 (HGNC:28401): (RNA binding motif protein 46) Predicted to enable mRNA binding activity. Predicted to act upstream of or within mRNA stabilization and trophectodermal cell differentiation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RBM46 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021885127).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM46	NM_144979.5 link	c.476A>G	p.Asp159Gly	missense_variant	Exon 3 of 5	ENST00000281722.8	NP_659416.1	Q8TBY0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBM46	ENST00000281722.8 link	c.476A>G	p.Asp159Gly	missense_variant	Exon 3 of 5	1	NM_144979.5	ENSP00000281722.3	Q8TBY0-1
RBM46	ENST00000514866.5 link	c.476A>G	p.Asp159Gly	missense_variant	Exon 3 of 6	2		ENSP00000424500.1	Q8TBY0-3
RBM46	ENST00000510397.5 link	c.476A>G	p.Asp159Gly	missense_variant	Exon 3 of 5	2		ENSP00000422813.1	Q8TBY0-2
RBM46	ENST00000512640.1 link	c.*77A>G		downstream_gene_variant		4		ENSP00000426672.1	D6RF41

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.000478

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250864

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.000994

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461580

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000414

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000915

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:

0.000473

Alfa

AF:

0.0000607

Hom.:

Bravo

AF:

0.000480

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476A>G (p.D159G) alteration is located in exon 3 (coding exon 2) of the RBM46 gene. This alteration results from a A to G substitution at nucleotide position 476, causing the aspartic acid (D) at amino acid position 159 to be replaced by a glycine (G). 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

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

.;T;.

Eigen

Benign

-0.019

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0049

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.66

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.064

Sift

Benign

0.031

D;D;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.28

MVP

0.33

MPC

1.6

ClinPred

0.034

GERP RS

5.8

Varity_R

0.22

gMVP

0.66

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