chr17-81934670-C-A

Variant names:

• chr17-81934670-C-A
• rs121918375
• NM_006907.4:c.616G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. 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
• Publications: 7 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-81934670-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 13191.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006907.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR1	NM_006907.4	MANE Select	c.616G>T	p.Gly206Trp	missense	Exon 5 of 7	NP_008838.2
	PYCR1	NM_001282281.2		c.697G>T	p.Gly233Trp	missense	Exon 6 of 8	NP_001269210.1
	PYCR1	NM_001282280.2		c.616G>T	p.Gly206Trp	missense	Exon 6 of 8	NP_001269209.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR1	ENST00000329875.13	TSL:1 MANE Select	c.616G>T	p.Gly206Trp	missense	Exon 5 of 7	ENSP00000328858.8
	PYCR1	ENST00000619204.4	TSL:1	c.616G>T	p.Gly206Trp	missense	Exon 6 of 8	ENSP00000479793.1
	PYCR1	ENST00000337943.9	TSL:1	c.616G>T	p.Gly206Trp	missense	Exon 5 of 8	ENSP00000336579.5

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

African (AFR) AF: 0.00 AC: 0 AN: 32326

American (AMR) AF: 0.00 AC: 0 AN: 39074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 37170

South Asian (SAS) AF: 0.00 AC: 0 AN: 80904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092076

Other (OTH) AF: 0.00 AC: 0 AN: 58824

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

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.91		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918375; hg19: chr17-79892546;