dbSNP rs771578999: PRR18:p.Glu252Asp (chr6-166307387-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_175922.4(PRR18):c.756G>T(p.Glu252Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,578,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PRR18
NM_175922.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0360

Publications

0 publications found

Variant links:

Genes affected

PRR18 (HGNC:28574): (proline rich 18)

PRR18 links:

LOC107986669 (HGNC:):

LOC107986669 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20928219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4 link	c.756G>T	p.Glu252Asp	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2	Q8N4B5
LOC107986669	XR_001744464.2 link	n.-161C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5 link	c.756G>T	p.Glu252Asp	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3		Q8N4B5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426072

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30426

American (AMR)

AF:

0.00

AC:

AN:

42404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25360

East Asian (EAS)

AF:

0.00

AC:

AN:

36628

South Asian (SAS)

AF:

0.00

AC:

AN:

83424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102200

Other (OTH)

AF:

0.00

AC:

AN:

59320

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

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.756G>T (p.E252D) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a G to T substitution at nucleotide position 756, causing the glutamic acid (E) at amino acid position 252 to be replaced by an aspartic acid (D). 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

0.83

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

0.029

Eigen_PC

Benign

-0.047

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

PhyloP100

0.036

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.87

Vest4

0.17

MutPred

0.21

Loss of helix (P = 0.1706);

MVP

0.092

MPC

1.3

ClinPred

0.99

GERP RS

0.17

Varity_R

0.68

gMVP

0.094

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

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rs771578999

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over