Genetic Variant RBM45:p.Ala326Val (chr2-178123645-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152945.4(RBM45):c.977C>T(p.Ala326Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RBM45
NM_152945.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

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_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06347215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM45	NM_152945.4 link	c.977C>T	p.Ala326Val	missense_variant	Exon 6 of 10	ENST00000286070.10	NP_694453.2	Q8IUH3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBM45	ENST00000286070.10 link	c.977C>T	p.Ala326Val	missense_variant	Exon 6 of 10	1	NM_152945.4	ENSP00000286070.5	Q8IUH3-3
RBM45	ENST00000424000.6 link	n.1100C>T		non_coding_transcript_exon_variant	Exon 6 of 9	2
RBM45	ENST00000493048.1 link	n.480C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3
RBM45	ENST00000455903.6 link	c.-220C>T		upstream_gene_variant		3		ENSP00000415940.1	H7C476

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1452580

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722214

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000606

AC:

AN:

32986

American (AMR)

AF:

0.00

AC:

AN:

42952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25466

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

83894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108826

Other (OTH)

AF:

0.00

AC:

AN:

60022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

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

Jul 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.977C>T (p.A326V) alteration is located in exon 6 (coding exon 6) of the RBM45 gene. This alteration results from a C to T substitution at nucleotide position 977, causing the alanine (A) at amino acid position 326 to be replaced by a valine (V). 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

0.15

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.063

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;.

PhyloP100

2.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.77

.;N

REVEL

Benign

0.059

Sift

Benign

0.29

.;T

Sift4G

Benign

0.33

T;T

Polyphen

0.010

.;B

Vest4

0.15

MutPred

0.32

.;Loss of disorder (P = 0.1085);

MVP

0.20

MPC

0.54

ClinPred

0.13

GERP RS

2.6

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.025

gMVP

0.33

Mutation Taster

=97/3

polymorphism

(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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chr2-178123645-C-T

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