19-35802983-C-A

Variant names:

• chr19-35802983-C-A
• rs149481373
• NM_021232.2:c.1097G>T

Variant summary

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

The NM_021232.2(PRODH2):​c.1097G>T​(p.Arg366Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,561,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: PRODH2 NM_021232.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.25

Genes affected

PRODH2 (HGNC:17325): (proline dehydrogenase 2) The protein encoded by this gene catalyzes the first step in the catabolism of trans-4-hydroxy-L-proline, an amino acid derivative obtained through food intake and collagen turnover. One of the downstream products of this catabolism is glyoxylate, which in people with disorders of glyoxalate metabolism can lead to an increase in oxalate levels and the formation of calcium-oxalate kidney stones. Therefore, this gene may serve as a therapeutic target against primary hyperoxalurias (PH). This gene is similar to proline dehydrogenase (oxidase) 1, a mitochondrial enzyme that catalyzes the first step in proline catabolism. [provided by RefSeq, Jan 2017]

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=0.15427881).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH2	NM_021232.2	c.1097G>T	p.Arg366Leu	missense_variant	Exon 8 of 10	ENST00000653904.2	NP_067055.2
PRODH2	NM_001378292.1	c.941G>T	p.Arg314Leu	missense_variant	Exon 7 of 9		NP_001365221.1
PRODH2	NM_001378293.1	c.1097G>T	p.Arg366Leu	missense_variant	Exon 8 of 9		NP_001365222.1
PRODH2	NM_001378294.1	c.941G>T	p.Arg314Leu	missense_variant	Exon 7 of 8		NP_001365223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH2	ENST00000653904.2	c.1097G>T	p.Arg366Leu	missense_variant	Exon 8 of 10		NM_021232.2	ENSP00000499779.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000154 AC: 3 AN: 194896 Hom.: 0 AF XY: 0.0000288 AC XY: 3 AN XY: 104302

Gnomad AFR exome AF: 0.0000814

Gnomad AMR exome AF: 0.0000710

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000497 AC: 7 AN: 1409678 Hom.: 0 Cov.: 30 AF XY: 0.00000576 AC XY: 4 AN XY: 694174

Gnomad4 AFR exome AF: 0.0000918

Gnomad4 AMR exome AF: 0.0000511

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74466

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1325G>T (p.R442L) alteration is located in exon 9 (coding exon 9) of the PRODH2 gene. This alteration results from a G to T substitution at nucleotide position 1325, causing the arginine (R) at amino acid position 442 to be replaced by a leucine (L). 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	0.097
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.78
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D;D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.14
Sift	Benign	0.042	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.025	B;.
Vest4		0.28
MutPred		0.63		Loss of disorder (P = 0.0452);.;
MVP		0.11
MPC		0.18
ClinPred		0.067	T
GERP RS		-11
Varity_R		0.19
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149481373; hg19: chr19-36293885;