6-166307560-G-A

Variant names:

• chr6-166307560-G-A
• rs577902206
• NM_175922.4:c.583C>T

Variant summary

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

The NM_175922.4(PRR18):​c.583C>T​(p.Pro195Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,211,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: PRR18 NM_175922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 0 publications found

Genes affected

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

LOC107986669 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04478237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4	c.583C>T	p.Pro195Ser	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2
LOC107986669	XR_001744464.2	n.13G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5	c.583C>T	p.Pro195Ser	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3
PRR18	ENST00000529616.1	c.*233C>T		downstream_gene_variant		2		ENSP00000433381.1

Frequencies

GnomAD3 genomes AF: 0.000167 AC: 25 AN: 149984 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00234

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1024 AF XY: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000951 AC: 101 AN: 1061666 Hom.: 0 Cov.: 59 AF XY: 0.0000936 AC XY: 47 AN XY: 502046

African (AFR) AF: 0.00 AC: 0 AN: 21938

American (AMR) AF: 0.000261 AC: 2 AN: 7650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13170

East Asian (EAS) AF: 0.000926 AC: 23 AN: 24834

South Asian (SAS) AF: 0.00 AC: 0 AN: 20194

European-Finnish (FIN) AF: 0.000331 AC: 7 AN: 21130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2868

European-Non Finnish (NFE) AF: 0.0000705 AC: 64 AN: 907842

Other (OTH) AF: 0.000119 AC: 5 AN: 42040

GnomAD4 genome AF: 0.000160 AC: 24 AN: 150092 Hom.: 0 Cov.: 33 AF XY: 0.000218 AC XY: 16 AN XY: 73296

African (AFR) AF: 0.0000484 AC: 2 AN: 41284

American (AMR) AF: 0.0000663 AC: 1 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00215 AC: 11 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000149 AC: 10 AN: 67318

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000185

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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.583C>T (p.P195S) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a C to T substitution at nucleotide position 583, causing the proline (P) at amino acid position 195 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.061
Sift	Benign	0.043	D
Sift4G	Benign	0.49	T
Polyphen		0.71	P
Vest4		0.093
MutPred		0.18		Gain of phosphorylation at P195 (P = 0.0066);
MVP		0.081
MPC		1.9
ClinPred		0.62	D
GERP RS		1.9
Varity_R		0.068
gMVP		0.10
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs577902206; hg19: chr6-166721048;