10-13611673-A-G

Variant names:

• chr10-13611673-A-G
• NM_003675.4:c.569A>G

Variant summary

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

The NM_003675.4(PRPF18):​c.569A>G​(p.Lys190Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: PRPF18 NM_003675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.51
• Publications: 0 publications found

Genes affected

PRPF18 (HGNC:17351): (pre-mRNA processing factor 18) Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is found to be essential for the catalytic step II in pre-mRNA splicing process. It is found in the spliceosome, and contains seven WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to the yeast splicing factor Prp18. [provided by RefSeq, Jul 2008]

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=0.35563517).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003675.4. 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
	PRPF18	NM_003675.4	MANE Select	c.569A>G	p.Lys190Arg	missense	Exon 6 of 10	NP_003666.1	Q99633-1
	PRPF18	NM_001395875.1		c.596A>G	p.Lys199Arg	missense	Exon 7 of 11	NP_001382804.1
	PRPF18	NM_001395876.1		c.551A>G	p.Lys184Arg	missense	Exon 8 of 12	NP_001382805.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF18	ENST00000378572.8	TSL:1 MANE Select	c.569A>G	p.Lys190Arg	missense	Exon 6 of 10	ENSP00000367835.3	Q99633-1
	PRPF18	ENST00000937338.1		c.569A>G	p.Lys190Arg	missense	Exon 6 of 11	ENSP00000607397.1
	PRPF18	ENST00000855616.1		c.596A>G	p.Lys199Arg	missense	Exon 7 of 11	ENSP00000525675.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	0.088
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		8.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.17
Sift	Benign	0.37	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.59
MutPred		0.53		Loss of methylation at K190 (P = 0.0109)
MVP		0.49
MPC		0.72
ClinPred		0.77	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.53
Mutation Taster		=71/29	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: chr10-13653673;