17-81935132-G-C

Variant names:

• chr17-81935132-G-C
• rs147653673
• NM_006907.4:c.334C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006907.4(PYCR1):​c.334C>G​(p.Arg112Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,570 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. R112W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PYCR1 NM_006907.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14
• Publications: 0 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• PYCR1-related de Barsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
• geroderma osteodysplastica

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_006907.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21646464).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR1	NM_006907.4	MANE Select	c.334C>G	p.Arg112Gly	missense	Exon 4 of 7	NP_008838.2
	PYCR1	NM_001282281.2		c.415C>G	p.Arg139Gly	missense	Exon 5 of 8	NP_001269210.1	P32322-3
	PYCR1	NM_001282280.2		c.334C>G	p.Arg112Gly	missense	Exon 5 of 8	NP_001269209.1	P32322-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYCR1	ENST00000329875.13	TSL:1 MANE Select	c.334C>G	p.Arg112Gly	missense	Exon 4 of 7	ENSP00000328858.8	P32322-1
	PYCR1	ENST00000619204.4	TSL:1	c.334C>G	p.Arg112Gly	missense	Exon 5 of 8	ENSP00000479793.1	P32322-1
	PYCR1	ENST00000337943.9	TSL:1	c.334C>G	p.Arg112Gly	missense	Exon 4 of 8	ENSP00000336579.5	P32322-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455570 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724266

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5316

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111714

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.77
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PhyloP100		6.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.31	T
Sift4G	Benign	0.40	T
Polyphen		0.090	B
Vest4		0.41
MutPred		0.56		Loss of MoRF binding (P = 0.0051)
MVP		0.68
MPC		0.16
ClinPred		0.32	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.58

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: rs147653673; hg19: chr17-79893008;