Genetic Variant PRR18:p.Leu295Gln (chr6-166307259-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_175922.4(PRR18):c.884T>A(p.Leu295Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000598 in 1,337,058 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: not found (cov: 34)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

PRR18
NM_175922.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.656

Publications

0 publications found

Variant links:

Genes affected

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

PRR18 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11632839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4 link	c.884T>A	p.Leu295Gln	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2	Q8N4B5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5 link	c.884T>A	p.Leu295Gln	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3		Q8N4B5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

91056

AF XY:

0.0000192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000598

AC:

AN:

1337058

Hom.:

Cov.:

AF XY:

0.00000303

AC XY:

AN XY:

660020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27330

American (AMR)

AF:

0.000285

AC:

AN:

28048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22390

East Asian (EAS)

AF:

0.00

AC:

AN:

30756

South Asian (SAS)

AF:

0.00

AC:

AN:

72530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4158

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060574

Other (OTH)

AF:

0.00

AC:

AN:

55682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000185

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.884T>A (p.L295Q) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a T to A substitution at nucleotide position 884, causing the leucine (L) at amino acid position 295 to be replaced by a glutamine (Q). 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

0.63

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.0

PhyloP100

0.66

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.33

MutPred

0.32

Loss of stability (P = 0.0063);

MVP

0.40

MPC

2.0

ClinPred

0.73

GERP RS

3.5

Varity_R

0.76

gMVP

0.059

Mutation Taster

=84/16

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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6-166307259-A-T

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