Genetic Variant PRR18:p.Ala207Thr (chr6-166307524-C-T) – 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.619G>A(p.Ala207Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,225,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A207G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PRR18
NM_175922.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0300

Variant links:

Genes affected

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

PRR18 links:

LOC107986669 (HGNC:):

LOC107986669 links:

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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=0.020805001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4 link	c.619G>A	p.Ala207Thr	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2	Q8N4B5
LOC107986669	XR_001744464.2 link	n.-24C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5 link	c.619G>A	p.Ala207Thr	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3		Q8N4B5

Frequencies

GnomAD3 genomes

AF:

0.000153

AC:

AN:

150352

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000267

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000590

AC:

AN:

1696

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000254

AC:

273

AN:

1075396

Hom.:

Cov.:

AF XY:

0.000247

AC XY:

126

AN XY:

510242

show subpopulations

African (AFR)

AF:

0.000135

AC:

AN:

22292

American (AMR)

AF:

0.00

AC:

AN:

7782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13546

East Asian (EAS)

AF:

0.00

AC:

AN:

25088

South Asian (SAS)

AF:

0.00

AC:

AN:

21802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2964

European-Non Finnish (NFE)

AF:

0.000287

AC:

263

AN:

917772

Other (OTH)

AF:

0.000164

AC:

AN:

42680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000153

AC:

AN:

150352

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

AN XY:

73360

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41174

American (AMR)

AF:

0.00

AC:

AN:

15092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000267

AC:

AN:

67530

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000159

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.619G>A (p.A207T) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a G to A substitution at nucleotide position 619, causing the alanine (A) at amino acid position 207 to be replaced by a threonine (T). 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

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.8

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.021

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.30

M_CAP

Benign

0.050

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.030

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.79

REVEL

Benign

0.024

Sift

Benign

0.43

Sift4G

Benign

0.20

Polyphen

0.19

Vest4

0.025

MutPred

0.21

Gain of phosphorylation at A207 (P = 9e-04);

MVP

0.030

MPC

0.92

ClinPred

0.028

GERP RS

0.0089

Varity_R

0.040

gMVP

0.057

Mutation Taster

=99/1

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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6-166307524-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over