rs121918378

Variant names:

• chr17-81934371-C-A
• rs121918378
• NM_006907.4:c.752G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-81934371-C-A
• chr17-81934371-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_006907.4(PYCR1):​c.752G>T​(p.Arg251Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYCR1 NM_006907.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr17-81934372-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 986091.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

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.752G>T	p.Arg251Leu	missense	Exon 6 of 7	NP_008838.2
	PYCR1	NM_001282281.2		c.833G>T	p.Arg278Leu	missense	Exon 7 of 8	NP_001269210.1	P32322-3
	PYCR1	NM_001282280.2		c.752G>T	p.Arg251Leu	missense	Exon 7 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.752G>T	p.Arg251Leu	missense	Exon 6 of 7	ENSP00000328858.8	P32322-1
	PYCR1	ENST00000619204.4	TSL:1	c.752G>T	p.Arg251Leu	missense	Exon 7 of 8	ENSP00000479793.1	P32322-1
	PYCR1	ENST00000337943.9	TSL:1	c.752G>T	p.Arg251Leu	missense	Exon 6 of 8	ENSP00000336579.5	P32322-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.80		Loss of catalytic residue at R251 (P = 0.0598)
MVP		0.98
MPC		0.64
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.92
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918378; hg19: chr17-79892247;