Genetic Variant NM_023078.6:c.16C>G (chr8-143609533-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_023078.6(PYCR3):c.16C>G(p.Pro6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,359,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PYCR3
NM_023078.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.79

Publications

2 publications found

Variant links:

Genes affected

PYCR3 (HGNC:25846): (pyrroline-5-carboxylate reductase 3) This gene encodes a protein that belongs to the pyrroline-5-carboxylate reductase family of enzymes. Members of this family catalyze the final step in proline biosynthesis, converting pyrroline-5-carboxylate to proline. Glutamate and ornithine are precursors in the synthesis of proline. The protein encoded by this gene is a cytoplasmic enzyme involved in the biosynthesis of proline from ornithine. [provided by RefSeq, Aug 2016]

PYCR3 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0430564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR3	NM_023078.6 link	c.16C>G	p.Pro6Ala	missense_variant	Exon 1 of 6	ENST00000495276.6	NP_075566.3	Q53H96-1A0A0A0MQS1
PYCR3	NM_001329866.3 link	c.16C>G	p.Pro6Ala	missense_variant	Exon 1 of 6		NP_001316795.2	Q53H96-2B4DGI7
PYCR3	NR_138144.3 link	n.43C>G		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR3	ENST00000495276.6 link	c.16C>G	p.Pro6Ala	missense_variant	Exon 1 of 6	1	NM_023078.6	ENSP00000480945.1		Q53H96-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000944

AC:

AN:

105896

AF XY:

0.0000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000251

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1359118

Hom.:

Cov.:

AF XY:

0.00000298

AC XY:

AN XY:

670986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27752

American (AMR)

AF:

0.00

AC:

AN:

33342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24076

East Asian (EAS)

AF:

0.00

AC:

AN:

32076

South Asian (SAS)

AF:

0.00

AC:

AN:

76772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5068

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1069550

Other (OTH)

AF:

0.00

AC:

AN:

56610

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.050

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.0024

T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.053

M_CAP

Benign

0.039

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.57

.;N;N

PhyloP100

-1.8

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.46

N;.;.

REVEL

Benign

0.082

Sift

Benign

0.47

T;.;.

Sift4G

Benign

0.83

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.068

MutPred

0.26

.;Loss of glycosylation at P6 (P = 0.0148);Loss of glycosylation at P6 (P = 0.0148);

MVP

0.12

MPC

0.20

ClinPred

0.065

GERP RS

-5.0

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.021

gMVP

0.16

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over