rs147653673

Positions:

chr17-81935132-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_006907.4(PYCR1):c.334C>T(p.Arg112Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,607,872 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

PYCR1
NM_006907.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

PYCR1 (HGNC:9721): (pyrroline-5-carboxylate reductase 1) This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

PYCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_006907.4

BP4

Computational evidence support a benign effect (MetaRNN=0.024432719).

BP6

Variant 17-81935132-G-A is Benign according to our data. Variant chr17-81935132-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282265.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000978 (149/152306) while in subpopulation SAS AF= 0.00248 (12/4830). AF 95% confidence interval is 0.00151. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYCR1	NM_006907.4 linkuse as main transcript	c.334C>T	p.Arg112Trp	missense_variant	4/7	ENST00000329875.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYCR1	ENST00000329875.13 linkuse as main transcript	c.334C>T	p.Arg112Trp	missense_variant	4/7	1	NM_006907.4	P1	P32322-1

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000832

AC:

203

AN:

244016

Hom.:

AF XY:

0.000895

AC XY:

119

AN XY:

133020

show subpopulations

Gnomad AFR exome

AF:

0.000316

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000722

Gnomad FIN exome

AF:

0.000330

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.00157

AC:

2287

AN:

1455566

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1126

AN XY:

724264

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000824

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.000697

GnomAD4 genome

AF:

0.000978

AC:

149

AN:

152306

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000756

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000850

AC:

103

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PYCR1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -

Cutis laxa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal recessive cutis laxa type 2B;C3280799:PYCR1-related de Barsy syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;.;.;T;.;T;.;T;T;T;.;T;T;T

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.077

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

.;D;D;D;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.024

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

L;L;.;.;L;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.96

N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

N;N;N;.;.;.;.;N;.;.;.;.;.;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.027

D;D;D;.;.;.;.;T;.;.;.;.;.;.;.

Sift4G

Uncertain

0.031

D;D;D;T;D;T;T;D;.;D;.;.;T;.;.

Polyphen

0.96

D;.;.;.;D;.;.;.;.;.;.;.;.;.;.

Vest4

0.45

MVP

0.78

MPC

0.18

ClinPred

0.084

GERP RS

4.1

Varity_R

0.12

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over