Genetic Variant PRR18:p.Ser275Ala (chr6-166307320-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_175922.4(PRR18):c.823T>G(p.Ser275Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S275C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRR18
NM_175922.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.671

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054107666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4 link	c.823T>G	p.Ser275Ala	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2	Q8N4B5
LOC107986669	XR_001744464.2 link	n.-228A>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5 link	c.823T>G	p.Ser275Ala	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3		Q8N4B5

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000955

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1403634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696700

African (AFR)

AF:

0.00

AC:

AN:

29826

American (AMR)

AF:

0.00

AC:

AN:

39682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24870

East Asian (EAS)

AF:

0.00

AC:

AN:

35392

South Asian (SAS)

AF:

0.00

AC:

AN:

80952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092090

Other (OTH)

AF:

0.00

AC:

AN:

58426

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000331

AC:

AN:

151092

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73778

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41090

American (AMR)

AF:

0.0000656

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.0000955

AC:

AN:

10474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67666

Other (OTH)

AF:

0.00

AC:

AN:

2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.823T>G (p.S275A) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a T to G substitution at nucleotide position 823, causing the serine (S) at amino acid position 275 to be replaced by an alanine (A). 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

Benign

0.096

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.071

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.37

M_CAP

Benign

0.060

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.67

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.053

Sift

Uncertain

0.019

Sift4G

Uncertain

0.042

Polyphen

0.018

Vest4

0.081

MutPred

0.30

Gain of helix (P = 0.027);

MVP

0.040

MPC

0.98

ClinPred

0.079

GERP RS

-1.3

Varity_R

0.11

gMVP

0.045

Mutation Taster

=92/8

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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chr6-166307320-A-C

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