8-143606082-T-A

Position:

• chr8-143606082-T-A

Variant summary

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

The NM_023078.6(PYCR3):​c.622A>T​(p.Ile208Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYCR3 NM_023078.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

Genes affected

PYCR3 (HGNC:25846): (pyrroline-5-carboxylate reductase 3) This gene encodes a protein that belongs to the pyrroline-5-carboxylate reductase family of enzymes. Members of this family catalyze the final step in proline biosynthesis, converting pyrroline-5-carboxylate to proline. Glutamate and ornithine are precursors in the synthesis of proline. The protein encoded by this gene is a cytoplasmic enzyme involved in the biosynthesis of proline from ornithine. [provided by RefSeq, Aug 2016]

PYCR3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYCR3	NM_023078.6	c.622A>T	p.Ile208Phe	missense_variant	5/6	ENST00000495276.6	NP_075566.3
PYCR3	NM_001329866.3	c.562A>T	p.Ile188Phe	missense_variant	5/6		NP_001316795.2
PYCR3	NR_138144.3	n.762A>T		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYCR3	ENST00000495276.6	c.622A>T	p.Ile208Phe	missense_variant	5/6	1	NM_023078.6	ENSP00000480945.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.658A>T (p.I220F) alteration is located in exon 5 (coding exon 5) of the PYCRL gene. This alteration results from a A to T substitution at nucleotide position 658, causing the isoleucine (I) at amino acid position 220 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.072	T;T;.;D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	.;N;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N;.;.;N
REVEL	Uncertain	0.57
Sift	Benign	0.14	T;.;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.049	.;B;.;.
Vest4		0.42
MutPred		0.84		.;Gain of methylation at R207 (P = 0.0853);.;.;
MVP		0.72
MPC		0.40
ClinPred		0.72	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.92

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: rs934310514; hg19: chr8-144688252;