17-81932942-C-T

Position:

• chr17-81932942-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153824.3(PYCR1):​c.889G>A​(p.Gly297Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,611,660 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (201 hom.)
• Consequence: PYCR1 NM_153824.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10

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]

ENSG00000263585 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018904805).
• BP6: Variant 17-81932942-C-T is Benign according to our data. Variant chr17-81932942-C-T is described in ClinVar as [Benign]. Clinvar id is 325898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYCR1	NM_006907.4	c.*272G>A		3_prime_UTR_variant	7/7	ENST00000329875.13	NP_008838.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR1	ENST00000329875	c.*272G>A		3_prime_UTR_variant	7/7	1	NM_006907.4	ENSP00000328858.8

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1536 AN: 152206 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0556

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0151 AC: 3694 AN: 245330 Hom.: 146 AF XY: 0.0117 AC XY: 1554 AN XY: 133180

Gnomad AFR exome AF: 0.00998

Gnomad AMR exome AF: 0.0806

Gnomad ASJ exome AF: 0.000608

Gnomad EAS exome AF: 0.0321

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.000824

Gnomad NFE exome AF: 0.000559

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.00426 AC: 6216 AN: 1459336 Hom.: 201 Cov.: 30 AF XY: 0.00379 AC XY: 2753 AN XY: 725750

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0752

Gnomad4 ASJ exome AF: 0.000614

Gnomad4 EAS exome AF: 0.0446

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.000974

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.0101 AC: 1539 AN: 152324 Hom.: 28 Cov.: 33 AF XY: 0.0113 AC XY: 838 AN XY: 74488

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.0556

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0299

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00300 Hom.: 7

Bravo AF: 0.0146

ESP6500AA AF: 0.00773 AC: 34

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0121 AC: 1469

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cutis laxa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.0
DANN	Benign	0.70
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.94	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.17
Sift	Benign	0.073	T
Sift4G	Benign	0.11	T
Vest4		0.057
MutPred		0.17		Loss of glycosylation at S298 (P = 0.0963);
ClinPred		0.0029	T
GERP RS		-5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs3744807; hg19: chr17-79890818; COSMIC: COSV61696023; COSMIC: COSV61696023;