17-81933225-C-T

Position:

• chr17-81933225-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006907.4(PYCR1):​c.949G>A​(p.Gly317Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYCR1 NM_006907.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15778416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYCR1	NM_006907.4	c.949G>A	p.Gly317Ser	missense_variant	7/7	ENST00000329875.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYCR1	ENST00000329875.13	c.949G>A	p.Gly317Ser	missense_variant	7/7	1	NM_006907.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PYCR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 317 of the PYCR1 protein (p.Gly317Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.14	T;.;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.5	L;.;L;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.34	N;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.093	T;.;.;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.094	B;.;B;.
Vest4		0.16
MutPred		0.15		Gain of phosphorylation at G317 (P = 0.0089);.;Gain of phosphorylation at G317 (P = 0.0089);.;
MVP		0.87
MPC		0.12
ClinPred		0.22	T
GERP RS		3.6
Varity_R		0.078
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-79891101;