NM_006907.4:c.*352C>G

Variant names:

• chr17-81932862-G-C
• rs149456432
• NM_006907.4:c.*352C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_006907.4(PYCR1):​c.*352C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,602,872 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: PYCR1 NM_006907.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.415
• 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

PYCR1-AS1 (HGNC:56889):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0014 (214/152362) while in subpopulation NFE AF = 0.00248 (169/68038). AF 95% confidence interval is 0.00218. There are 2 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.*352C>G		3_prime_UTR	Exon 7 of 7	NP_008838.2
	PYCR1	NM_001282281.2		c.*352C>G		3_prime_UTR	Exon 8 of 8	NP_001269210.1	P32322-3
	PYCR1	NM_001282280.2		c.*352C>G		3_prime_UTR	Exon 8 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.*352C>G		3_prime_UTR	Exon 7 of 7	ENSP00000328858.8	P32322-1
	PYCR1	ENST00000619204.4	TSL:1	c.*352C>G		3_prime_UTR	Exon 8 of 8	ENSP00000479793.1	P32322-1
	PYCR1	ENST00000337943.9	TSL:1	c.*18C>G		3_prime_UTR	Exon 8 of 8	ENSP00000336579.5	P32322-2

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000898 AC: 208 AN: 231652 AF XY: 0.000868

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.000273

Gnomad ASJ exome AF: 0.000419

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000985

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.000696

GnomAD4 exome AF: 0.00161 AC: 2333 AN: 1450510 Hom.: 2 Cov.: 30 AF XY: 0.00157 AC XY: 1129 AN XY: 720538

African (AFR) AF: 0.000360 AC: 12 AN: 33316

American (AMR) AF: 0.000276 AC: 12 AN: 43426

Ashkenazi Jewish (ASJ) AF: 0.000310 AC: 8 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.0000710 AC: 6 AN: 84486

European-Finnish (FIN) AF: 0.000842 AC: 43 AN: 51056

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5584

European-Non Finnish (NFE) AF: 0.00197 AC: 2177 AN: 1107434

Other (OTH) AF: 0.00122 AC: 73 AN: 60014

GnomAD4 genome AF: 0.00140 AC: 214 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74504

African (AFR) AF: 0.000433 AC: 18 AN: 41584

American (AMR) AF: 0.000523 AC: 8 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00248 AC: 169 AN: 68038

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00158 Hom.: 1

Bravo AF: 0.00111

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cutis laxa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.67
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs149456432; hg19: chr17-79890738;