17-81932737-G-A

Position:

• chr17-81932737-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_006907.4(PYCR1):​c.*477C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,234,278 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (15 hom.)
• Consequence: PYCR1 NM_006907.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.148

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00242 (368/152356) while in subpopulation AMR AF= 0.00392 (60/15308). AF 95% confidence interval is 0.00313. There are 2 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYCR1	NM_006907.4	c.*477C>T		3_prime_UTR_variant	7/7	ENST00000329875.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYCR1	ENST00000329875.13	c.*477C>T		3_prime_UTR_variant	7/7	1	NM_006907.4	P1
	ENST00000583521.1	n.340G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00575

GnomAD4 exome AF: 0.00272 AC: 2940 AN: 1081922 Hom.: 15 Cov.: 15 AF XY: 0.00277 AC XY: 1503 AN XY: 542636

Gnomad4 AFR exome AF: 0.00107

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0000295

Gnomad4 SAS exome AF: 0.00309

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00248

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152356 Hom.: 2 Cov.: 33 AF XY: 0.00232 AC XY: 173 AN XY: 74500

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00281 Hom.: 1

Bravo AF: 0.00285

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cutis laxa Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.60
DANN	Benign	0.61

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: rs539637881; hg19: chr17-79890613;