Genetic Variant NM_003675.4:c.512C>A (chr10-13611616-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003675.4(PRPF18):c.512C>A(p.Ala171Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRPF18
NM_003675.4 missense, splice_region

Scores

Splicing: ADA: 0.0003738

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.47

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09249601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF18	NM_003675.4 link	c.512C>A	p.Ala171Glu	missense_variant, splice_region_variant	Exon 6 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.512C>A	p.Ala171Glu	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_003675.4	ENSP00000367835.3	Q99633-1
PRPF18	ENST00000417658.5 link	c.494C>A	p.Ala165Glu	missense_variant, splice_region_variant	Exon 8 of 10	5		ENSP00000392142.1	Q5T9P7
PRPF18	ENST00000601460.5 link	c.140C>A	p.Ala47Glu	missense_variant, splice_region_variant	Exon 2 of 7	5		ENSP00000473200.1	M0R3G1
PRPF18	ENST00000320054.4 link	c.467C>A	p.Ala156Glu	missense_variant, splice_region_variant	Exon 7 of 7	5		ENSP00000367824.1	Q5T9P8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.0067

T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0047

MetaRNN

Benign

0.092

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.98

L;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.97

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0030

B;.;.

Vest4

0.27

MutPred

0.33

Gain of disorder (P = 0.0552);.;.;

MVP

0.24

MPC

0.92

ClinPred

0.85

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00037

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over