NM_005778.4:c.1561C>A

Variant names:

• chr3-50113488-C-A
• rs1217712730
• NM_005778.4:c.1561C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_005778.4(RBM5):​c.1561C>A​(p.Pro521Thr) 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. 16/22 in silico tools predict a benign outcome for this variant. 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. P521S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBM5 NM_005778.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.431
• Publications: 0 publications found

Genes affected

RBM5 (HGNC:9902): (RNA binding motif protein 5) This gene is a candidate tumor suppressor gene which encodes a nuclear RNA binding protein that is a component of the spliceosome A complex. The encoded protein plays a role in the induction of cell cycle arrest and apoptosis through pre-mRNA splicing of multiple target genes including the tumor suppressor protein p53. This gene is located within the tumor suppressor region 3p21.3, and may play a role in the inhibition of tumor transformation and progression of several malignancies including lung cancer. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.1668 (above the threshold of 3.09). Trascript score misZ: 5.1927 (above the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.0525029).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005778.4. 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
	RBM5	NM_005778.4	MANE Select	c.1561C>A	p.Pro521Thr	missense	Exon 18 of 25	NP_005769.1	P52756-1
	RBM5	NR_036627.3		n.1651C>A		non_coding_transcript_exon	Exon 17 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM5	ENST00000347869.8	TSL:1 MANE Select	c.1561C>A	p.Pro521Thr	missense	Exon 18 of 25	ENSP00000343054.3	P52756-1
	RBM5	ENST00000852698.1		c.1561C>A	p.Pro521Thr	missense	Exon 18 of 26	ENSP00000522757.1
	RBM5	ENST00000852694.1		c.1567C>A	p.Pro523Thr	missense	Exon 18 of 25	ENSP00000522753.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.78
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.060	N
PhyloP100		0.43
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.027
Sift	Benign	0.21	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.18		Gain of phosphorylation at P521 (P = 0.0096)
MVP		0.17
MPC		1.0
ClinPred		0.26	T
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.027
gMVP		0.12
Mutation Taster		=96/4	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: rs1217712730; hg19: chr3-50150921;