rs121918375

Positions:

• chr17-81934670-C-A
• chr17-81934670-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_006907.4(PYCR1):​c.616G>T​(p.Gly206Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G206R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PYCR1 NM_006907.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 19) in uniprot entity P5CR1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006907.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 17-81934670-C-A is Pathogenic according to our data. Variant chr17-81934670-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13191.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-81934670-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYCR1	NM_006907.4	c.616G>T	p.Gly206Trp	missense_variant	5/7	ENST00000329875.13	NP_008838.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR1	ENST00000329875.13	c.616G>T	p.Gly206Trp	missense_variant	5/7	1	NM_006907.4	ENSP00000328858.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1420924 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 703222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive cutis laxa type 2B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;.;D;.;.;D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.6	L;L;.;L;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.0	D;D;.;.;.;D;.;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;D;.
Polyphen		1.0	D;.;.;D;.;.;.;.;.
Vest4		0.87
MutPred		0.91		Loss of methylation at R204 (P = 0.046);Loss of methylation at R204 (P = 0.046);Loss of methylation at R204 (P = 0.046);Loss of methylation at R204 (P = 0.046);Loss of methylation at R204 (P = 0.046);.;.;Loss of methylation at R204 (P = 0.046);Loss of methylation at R204 (P = 0.046);
MVP		0.93
MPC		0.62
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.97
gMVP		0.97

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

Other links and lift over

dbSNP: rs121918375; hg19: chr17-79892546;