chr2-178121307-A-G

Variant names:

• chr2-178121307-A-G
• NM_152945.4:c.801A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152945.4(RBM45):​c.801A>G​(p.Ile267Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 31)
• Consequence: RBM45 NM_152945.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.937
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34141114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBM45	NM_152945.4	c.801A>G	p.Ile267Met	missense_variant	Exon 5 of 10	ENST00000286070.10	NP_694453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM45	ENST00000286070.10	c.801A>G	p.Ile267Met	missense_variant	Exon 5 of 10	1	NM_152945.4	ENSP00000286070.5
RBM45	ENST00000424000.6	n.924A>G		non_coding_transcript_exon_variant	Exon 5 of 9	2
RBM45	ENST00000493048.1	n.304A>G		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.801A>G (p.I267M) alteration is located in exon 5 (coding exon 5) of the RBM45 gene. This alteration results from a A to G substitution at nucleotide position 801, causing the isoleucine (I) at amino acid position 267 to be replaced by a methionine (M). 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	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.082
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		0.94
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.12
Sift	Uncertain	0.021	.;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.92	.;P
Vest4		0.45
MutPred		0.47		.;Loss of catalytic residue at P269 (P = 0.0288);
MVP		0.51
MPC		1.1
ClinPred		0.88	D
GERP RS		1.9
Varity_R		0.20
gMVP		0.37
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

hg19: chr2-178986034;