2-178123633-A-G

Variant names:

• chr2-178123633-A-G
• rs767520459
• NM_152945.4:c.965A>G

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.72
• Publications: 0 publications found

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]

ACMG classification

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	c.965A>G	p.Asp322Gly	missense_variant	Exon 6 of 10	ENST00000286070.10	NP_694453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM45	ENST00000286070.10	c.965A>G	p.Asp322Gly	missense_variant	Exon 6 of 10	1	NM_152945.4	ENSP00000286070.5
RBM45	ENST00000424000.6	n.1088A>G		non_coding_transcript_exon_variant	Exon 6 of 9	2
RBM45	ENST00000493048.1	n.468A>G		non_coding_transcript_exon_variant	Exon 2 of 4	3
RBM45	ENST00000455903.6	c.-232A>G		upstream_gene_variant		3		ENSP00000415940.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454332 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 723208

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

African (AFR) AF: 0.00 AC: 0 AN: 33018

American (AMR) AF: 0.00 AC: 0 AN: 43068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25666

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109588

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		8.7
PrimateAI	Uncertain	0.64	T
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	D
GERP RS		4.7
PromoterAI		0.0036	Neutral
Varity_R		0.56
gMVP		0.67
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs767520459; hg19: chr2-178988360;