4-154827985-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_144979.5(RBM46):​c.1520C>T​(p.Pro507Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RBM46
NM_144979.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30573186).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBM46NM_144979.5 linkc.1520C>T p.Pro507Leu missense_variant Exon 5 of 5 ENST00000281722.8 NP_659416.1 Q8TBY0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBM46ENST00000281722.8 linkc.1520C>T p.Pro507Leu missense_variant Exon 5 of 5 1 NM_144979.5 ENSP00000281722.3 Q8TBY0-1
RBM46ENST00000510397.5 linkc.*1207C>T 3_prime_UTR_variant Exon 5 of 5 2 ENSP00000422813.1 Q8TBY0-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251228
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135774
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:
0.0000969
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461710
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
727158
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:
0.0000288
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 15, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1520C>T (p.P507L) alteration is located in exon 5 (coding exon 4) of the RBM46 gene. This alteration results from a C to T substitution at nucleotide position 1520, causing the proline (P) at amino acid position 507 to be replaced by a leucine (L). 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
0.12
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.040
T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.24
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.12
T
Polyphen
0.99
D
Vest4
0.31
MutPred
0.31
Loss of glycosylation at P507 (P = 0.0172);
MVP
0.39
MPC
0.087
ClinPred
0.31
T
GERP RS
5.7
Varity_R
0.090
gMVP
0.56

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.

Other links and lift over

dbSNP: rs777048083; hg19: chr4-155749137; COSMIC: COSV105159229; COSMIC: COSV105159229; API