Genetic Variant RBM45:p.Ala438Asp (chr2-178126064-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152945.4(RBM45):c.1313C>A(p.Ala438Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A438G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RBM45
NM_152945.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.83

Publications

0 publications found

Variant links:

Genes affected

RBM45 (HGNC:24468): (RNA binding motif protein 45) This gene encodes a member of the RNA recognition motif (RRM)-type RNA-binding family of proteins. This protein exhibits preferential binding to poly(C) RNA. Initial cloning of this gene found that the rat ortholog was dynamically expressed in the developing rat brain. This protein has been localized to inclusion bodies in the brain and spinal cord of amyotrophic lateral sclerosis and Alzheimer's patients. A pseudogene has been identified on chromosome 8. [provided by RefSeq, Feb 2015]

RBM45 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152945.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBM45	NM_152945.4	MANE Select	c.1313C>A	p.Ala438Asp	missense	Exon 9 of 10	NP_694453.2	Q8IUH3-3
RBM45	NM_001365579.1		c.1319C>A	p.Ala440Asp	missense	Exon 9 of 10	NP_001352508.1	Q8IUH3-1
RBM45	NM_001365578.1		c.1313C>A	p.Ala438Asp	missense	Exon 9 of 10	NP_001352507.1	Q8IUH3-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBM45	ENST00000286070.10	TSL:1 MANE Select	c.1313C>A	p.Ala438Asp	missense	Exon 9 of 10	ENSP00000286070.5	Q8IUH3-3
RBM45	ENST00000861657.1		c.1742C>A	p.Ala581Asp	missense	Exon 9 of 10	ENSP00000531716.1
RBM45	ENST00000953979.1		c.1742C>A	p.Ala581Asp	missense	Exon 9 of 10	ENSP00000624038.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251368

AF XY:

0.00

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 FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460728

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110988

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

4.1

PhyloP100

7.8

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.84

Gain of disorder (P = 0.0452)

MVP

0.55

MPC

1.8

ClinPred

1.0

GERP RS

5.7

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.62

gMVP

0.96

Mutation Taster

=15/85

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over