chr2-178123645-C-T

Variant names:

• chr2-178123645-C-T
• NM_152945.4:c.977C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• 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: 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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152945.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM45	NM_152945.4	MANE Select	c.977C>T	p.Ala326Val	missense	Exon 6 of 10	NP_694453.2	Q8IUH3-3
	RBM45	NM_001365579.1		c.983C>T	p.Ala328Val	missense	Exon 6 of 10	NP_001352508.1	Q8IUH3-1
	RBM45	NM_001365578.1		c.977C>T	p.Ala326Val	missense	Exon 6 of 10	NP_001352507.1	Q8IUH3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM45	ENST00000286070.10	TSL:1 MANE Select	c.977C>T	p.Ala326Val	missense	Exon 6 of 10	ENSP00000286070.5	Q8IUH3-3
	RBM45	ENST00000861657.1		c.1406C>T	p.Ala469Val	missense	Exon 6 of 10	ENSP00000531716.1
	RBM45	ENST00000953979.1		c.1406C>T	p.Ala469Val	missense	Exon 6 of 10	ENSP00000624038.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452580 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722214

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

African (AFR) AF: 0.0000606 AC: 2 AN: 32986

American (AMR) AF: 0.00 AC: 0 AN: 42952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 83894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108826

Other (OTH) AF: 0.00 AC: 0 AN: 60022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.059
Sift	Benign	0.29	T
Sift4G	Benign	0.33	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	T
GERP RS		2.6
PromoterAI		-0.027	Neutral
Varity_R		0.025
gMVP		0.33
Mutation Taster		=97/3	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

hg19: chr2-178988372;