Genetic Variant NM_144979.5:c.29A>T (chr4-154796781-A-T) – 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_144979.5(RBM46):c.29A>T(p.Asn10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RBM46
NM_144979.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56

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:

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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=0.24487048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM46	NM_144979.5 link	c.29A>T	p.Asn10Ile	missense_variant	Exon 2 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.29A>T	p.Asn10Ile	missense_variant	Exon 2 of 5	1	NM_144979.5	ENSP00000281722.3	Q8TBY0-1
RBM46	ENST00000514866.5 link	c.29A>T	p.Asn10Ile	missense_variant	Exon 2 of 6	2		ENSP00000424500.1	Q8TBY0-3
RBM46	ENST00000510397.5 link	c.29A>T	p.Asn10Ile	missense_variant	Exon 2 of 5	2		ENSP00000422813.1	Q8TBY0-2
RBM46	ENST00000512640.1 link	c.29A>T	p.Asn10Ile	missense_variant	Exon 2 of 3	4		ENSP00000426672.1	D6RF41

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248794

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134404

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726068

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29A>T (p.N10I) alteration is located in exon 2 (coding exon 1) of the RBM46 gene. This alteration results from a A to T substitution at nucleotide position 29, causing the asparagine (N) at amino acid position 10 to be replaced by an isoleucine (I). 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

0.095

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

.;T;.;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.0074

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;L;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.066

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.45

.;P;.;.

Vest4

0.47

MutPred

0.47

Loss of disorder (P = 0.02);Loss of disorder (P = 0.02);Loss of disorder (P = 0.02);Loss of disorder (P = 0.02);

MVP

0.35

MPC

1.9

ClinPred

0.56

GERP RS

5.7

Varity_R

0.24

gMVP

0.57

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