Genetic Variant NM_024321.5:c.725G>C (chr19-35633727-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024321.5(RBM42):c.725G>C(p.Gly242Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000006 in 1,334,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

RBM42
NM_024321.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Publications

0 publications found

Variant links:

Genes affected

RBM42 (HGNC:28117): (RNA binding motif protein 42) Enables RNA binding activity. Predicted to act upstream of or within negative regulation of mRNA splicing, via spliceosome. Predicted to be located in cytoplasm and nucleus. Predicted to be part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

RBM42 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3142572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM42	NM_024321.5 link	c.725G>C	p.Gly242Ala	missense_variant	Exon 7 of 10	ENST00000262633.9	NP_077297.2	Q9BTD8-1
RBM42	NM_001319113.2 link	c.638G>C	p.Gly213Ala	missense_variant	Exon 6 of 9		NP_001306042.1	Q9BTD8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM42	ENST00000262633.9 link	c.725G>C	p.Gly242Ala	missense_variant	Exon 7 of 10	1	NM_024321.5	ENSP00000262633.3		Q9BTD8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000600

AC:

AN:

1334418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

654846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26858

American (AMR)

AF:

0.00

AC:

AN:

24140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18882

East Asian (EAS)

AF:

0.00

AC:

AN:

33730

South Asian (SAS)

AF:

0.00

AC:

AN:

66402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5258

European-Non Finnish (NFE)

AF:

0.00000757

AC:

AN:

1056280

Other (OTH)

AF:

0.00

AC:

AN:

54692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Nov 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.725G>C (p.G242A) alteration is located in exon 7 (coding exon 7) of the RBM42 gene. This alteration results from a G to C substitution at nucleotide position 725, causing the glycine (G) at amino acid position 242 to be replaced by an alanine (A). 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

0.13

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

.;T;T;T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.;.;.

PhyloP100

3.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.28

.;N;.;.;.

REVEL

Benign

0.084

Sift

Uncertain

0.0040

.;D;.;.;.

Sift4G

Benign

0.88

T;T;T;T;T

Polyphen

1.0

D;B;.;.;.

Vest4

0.57

MutPred

0.13

.;Loss of loop (P = 0.0288);.;.;.;

MVP

0.25

MPC

0.30

ClinPred

0.74

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.062

gMVP

0.41

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_024321.5:c.725G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over