22-18913213-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_016335.6(PRODH):​c.1765C>T​(p.Arg589Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 2 hom., cov: 0)
Exomes 𝑓: 0.000012 ( 3 hom. )
Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

4
5
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.754
Variant links:
Genes affected
PRODH (HGNC:9453): (proline dehydrogenase 1) This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]
DGCR6 (HGNC:2846): (DiGeorge syndrome critical region gene 6) DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia. [provided by RefSeq, Nov 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.748
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000135 (4/29592) while in subpopulation SAS AF= 0.00274 (2/730). AF 95% confidence interval is 0.000487. There are 2 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 0. 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 rank MANE Protein UniProt
PRODHNM_016335.6 linkc.1765C>T p.Arg589Trp missense_variant Exon 14 of 14 ENST00000357068.11 NP_057419.5 O43272
PRODHNM_001195226.2 linkc.1441C>T p.Arg481Trp missense_variant Exon 14 of 14 NP_001182155.2 O43272
PRODHNM_001368250.2 linkc.1441C>T p.Arg481Trp missense_variant Exon 14 of 14 NP_001355179.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRODHENST00000357068.11 linkc.1765C>T p.Arg589Trp missense_variant Exon 14 of 14 1 NM_016335.6 ENSP00000349577.6 O43272
ENSG00000283809ENST00000638240.1 linkc.513+2185G>A intron_variant Intron 4 of 5 5 ENSP00000492446.1 A0A1W2PRQ8

Frequencies

GnomAD3 genomes
AF:
0.000136
AC:
4
AN:
29518
Hom.:
2
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00275
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000122
AC:
6
AN:
490868
Hom.:
3
Cov.:
0
AF XY:
0.0000166
AC XY:
4
AN XY:
241216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000285
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:
0.0000936
GnomAD4 genome
AF:
0.000135
AC:
4
AN:
29592
Hom.:
2
Cov.:
0
AF XY:
0.000139
AC XY:
2
AN XY:
14350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00274
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000189
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2021The c.1765C>T (p.R589W) alteration is located in exon 15 (coding exon 14) of the PRODH gene. This alteration results from a C to T substitution at nucleotide position 1765, causing the arginine (R) at amino acid position 589 to be replaced by a tryptophan (W). The p.R589W alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 10, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
D;.;.;D
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.50
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.82
T;.;T;.
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.75
D;D;D;D
MetaSVM
Benign
-0.48
T
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-6.7
.;D;D;D
REVEL
Uncertain
0.33
Sift
Pathogenic
0.0
.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.52
MutPred
0.76
Loss of disorder (P = 5e-04);.;.;Loss of disorder (P = 5e-04);
MVP
0.22
MPC
0.85
ClinPred
0.99
D
GERP RS
-0.84
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748701094; hg19: chr22-18900726; COSMIC: COSV58230403; COSMIC: COSV58230403; API