Genetic Variant NM_152945.4:c.965A>G (chr2-178123633-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152945.4(RBM45):c.965A>G(p.Asp322Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D322V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RBM45
NM_152945.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.72

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM45	NM_152945.4 link	c.965A>G	p.Asp322Gly	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.965A>G	p.Asp322Gly	missense_variant	Exon 6 of 10	1	NM_152945.4	ENSP00000286070.5	Q8IUH3-3
RBM45	ENST00000424000.6 link	n.1088A>G		non_coding_transcript_exon_variant	Exon 6 of 9	2
RBM45	ENST00000493048.1 link	n.468A>G		non_coding_transcript_exon_variant	Exon 2 of 4	3
RBM45	ENST00000455903.6 link	c.-232A>G		upstream_gene_variant		3		ENSP00000415940.1	H7C476

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454332

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723208

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33018

American (AMR)

AF:

0.00

AC:

AN:

43068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25666

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109588

Other (OTH)

AF:

0.00

AC:

AN:

60084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.071

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

PhyloP100

8.7

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.3

.;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.019

.;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

.;D

Vest4

0.80

MutPred

0.44

.;Gain of MoRF binding (P = 0.0917);

MVP

0.50

MPC

1.6

ClinPred

0.99

GERP RS

4.7

PromoterAI

0.0036

Neutral

(source)

Varity_R

0.56

gMVP

0.67

Mutation Taster

=58/42

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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NM_152945.4:c.965A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over