17-81935111-G-C

Variant names:

• chr17-81935111-G-C
• rs121918376
• NM_006907.4:c.355C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_006907.4(PYCR1):​c.355C>G​(p.Arg119Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,422 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R119H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PYCR1 NM_006907.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.39

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 Likely_pathogenic. Variant got 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 chr17-81935110-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-81935111-G-C is Pathogenic according to our data. Variant chr17-81935111-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13196.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-81935111-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYCR1	NM_006907.4	c.355C>G	p.Arg119Gly	missense_variant	Exon 4 of 7	ENST00000329875.13	NP_008838.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYCR1	ENST00000329875.13	c.355C>G	p.Arg119Gly	missense_variant	Exon 4 of 7	1	NM_006907.4	ENSP00000328858.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000811 AC: 2 AN: 246662 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457422 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 725118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;D;.;D;.;D;T;T;.;T;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	4.4	H;H;.;.;H;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.8	D;D;D;.;.;.;.;D;.;D;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;D;D;.;.;.;.;D;.;T;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;D;.;.;D;.
Polyphen		0.98	D;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.96
MutPred		0.98		Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);.;.;.;Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);.;Loss of MoRF binding (P = 0.0055);.;
MVP		0.86
MPC		0.59
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98

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: rs121918376; hg19: chr17-79892987; COSMIC: COSV99043407; COSMIC: COSV99043407;