Genetic Variant PRPF18:p.Val337Met (chr10-13630320-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_003675.4(PRPF18):c.1009G>A(p.Val337Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PRPF18
NM_003675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.46

Publications

0 publications found

Variant links:

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]

PRPF18 links:

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ACMG classification

Classification was made for transcript

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
PRPF18	NM_003675.4 link	c.1009G>A	p.Val337Met	missense_variant	Exon 10 of 10	ENST00000378572.8	NP_003666.1	Q99633-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRPF18	ENST00000378572.8 link	c.1009G>A	p.Val337Met	missense_variant	Exon 10 of 10	1	NM_003675.4	ENSP00000367835.3	Q99633-1
PRPF18	ENST00000595538.5 link	n.82G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000469146.1	M0QXG2
PRPF18	ENST00000596044.5 link	n.37G>A		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000469443.1	M0QXX3
PRPF18	ENST00000601460.5 link	c.576+13767G>A		intron_variant	Intron 5 of 6	5		ENSP00000473200.1	M0R3G1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725956

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109268

Other (OTH)

AF:

0.00

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1009G>A (p.V337M) alteration is located in exon 10 (coding exon 10) of the PRPF18 gene. This alteration results from a G to A substitution at nucleotide position 1009, causing the valine (V) at amino acid position 337 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.073

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

0.041

MutationAssessor

Uncertain

2.3

PhyloP100

8.5

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.67

MutPred

0.67

Loss of sheet (P = 0.0357);

MVP

0.61

MPC

1.7

ClinPred

0.96

GERP RS

5.7

Varity_R

0.27

gMVP

0.88

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over