2-178125986-G-A

Variant names:

• chr2-178125986-G-A
• rs767077878
• NM_152945.4:c.1235G>A

Variant summary

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

The NM_152945.4(RBM45):​c.1235G>A​(p.Arg412His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,610,284 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: RBM45 NM_152945.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.68
• Publications: 1 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.1235G>A	p.Arg412His	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000286070.10	NP_694453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM45	ENST00000286070.10	c.1235G>A	p.Arg412His	missense_variant, splice_region_variant	Exon 9 of 10	1	NM_152945.4	ENSP00000286070.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000522 AC: 13 AN: 249040 AF XY: 0.0000297

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000473 AC: 69 AN: 1458228 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 724992

African (AFR) AF: 0.0000300 AC: 1 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85926

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.0000559 AC: 62 AN: 1109764

Other (OTH) AF: 0.0000498 AC: 3 AN: 60248

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74264

African (AFR) AF: 0.0000725 AC: 3 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1235G>A (p.R412H) alteration is located in exon 9 (coding exon 9) of the RBM45 gene. This alteration results from a G to A substitution at nucleotide position 1235, causing the arginine (R) at amino acid position 412 to be replaced by a histidine (H). 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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		9.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.021	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.52		.;Loss of stability (P = 0.1776);
MVP		0.59
MPC		1.7
ClinPred		0.84	D
GERP RS		5.4
PromoterAI		-0.019	Neutral
Varity_R		0.50
gMVP		0.64
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs767077878; hg19: chr2-178990713; COSMIC: COSV53720563; COSMIC: COSV53720563;