Genetic Variant PYCR1:p.Arg266Leu (chr17-81934326-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_006907.4(PYCR1):c.797G>T(p.Arg266Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R266Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PYCR1
NM_006907.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive cutis laxa type 2B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
PYCR1-related de Barsy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, PanelApp Australia
geroderma osteodysplastica
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PYCR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-81934326-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR1	NM_006907.4 link	c.797G>T	p.Arg266Leu	missense_variant, splice_region_variant	Exon 6 of 7	ENST00000329875.13	NP_008838.2	P32322-1A0A024R8U9Q8TBX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR1	ENST00000329875.13 link	c.797G>T	p.Arg266Leu	missense_variant, splice_region_variant	Exon 6 of 7	1	NM_006907.4	ENSP00000328858.8		P32322-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460412

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.;D;.;D

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D;D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.56

D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.8

L;L;.;L;.;.

PhyloP100

3.7

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.1

D;D;.;.;D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0090

D;D;.;.;D;.

Sift4G

Uncertain

0.055

T;D;T;T;T;.

Polyphen

0.14

B;.;.;B;.;.

Vest4

0.68

MutPred

0.44

Loss of disorder (P = 0.0499);Loss of disorder (P = 0.0499);.;Loss of disorder (P = 0.0499);.;.;

MVP

0.96

MPC

0.24

ClinPred

0.98

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.77

Position offset: 0

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