rs3970559

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PS1_ModerateBP4_StrongBS1BS2

The NM_016335.6(PRODH):​c.1357C>T​(p.Arg453Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.018 ( 12 hom., cov: 4)
Exomes 𝑓: 0.013 ( 181 hom. )
Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

2
6
8

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:3O:1

Conservation

PhyloP100: 2.03
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PS1
Transcript NM_016335.6 (PRODH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
BP4
Computational evidence support a benign effect (MetaRNN=0.012216002).
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0125 (2640/211074) while in subpopulation AFR AF= 0.0384 (329/8564). AF 95% confidence interval is 0.035. There are 181 homozygotes in gnomad4_exome. There are 1348 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 181 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRODHNM_016335.6 linkc.1357C>T p.Arg453Cys missense_variant Exon 11 of 14 ENST00000357068.11 NP_057419.5 O43272
PRODHNM_001195226.2 linkc.1033C>T p.Arg345Cys missense_variant Exon 11 of 14 NP_001182155.2 O43272
PRODHNM_001368250.2 linkc.1033C>T p.Arg345Cys missense_variant Exon 11 of 14 NP_001355179.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRODHENST00000357068.11 linkc.1357C>T p.Arg453Cys missense_variant Exon 11 of 14 1 NM_016335.6 ENSP00000349577.6 O43272
ENSG00000283809ENST00000638240.1 linkc.513+7358G>A intron_variant Intron 4 of 5 5 ENSP00000492446.1 A0A1W2PRQ8

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
332
AN:
18570
Hom.:
12
Cov.:
4
FAILED QC
Gnomad AFR
AF:
0.0310
Gnomad AMI
AF:
0.0658
Gnomad AMR
AF:
0.0268
Gnomad ASJ
AF:
0.00602
Gnomad EAS
AF:
0.0160
Gnomad SAS
AF:
0.0113
Gnomad FIN
AF:
0.00289
Gnomad MID
AF:
0.0111
Gnomad NFE
AF:
0.00754
Gnomad OTH
AF:
0.0155
GnomAD3 exomes
AF:
0.0108
AC:
2704
AN:
249400
Hom.:
37
AF XY:
0.0106
AC XY:
1427
AN XY:
134932
show subpopulations
Gnomad AFR exome
AF:
0.0273
Gnomad AMR exome
AF:
0.0169
Gnomad ASJ exome
AF:
0.00737
Gnomad EAS exome
AF:
0.0137
Gnomad SAS exome
AF:
0.0106
Gnomad FIN exome
AF:
0.00320
Gnomad NFE exome
AF:
0.00802
Gnomad OTH exome
AF:
0.0110
GnomAD4 exome
AF:
0.0125
AC:
2640
AN:
211074
Hom.:
181
Cov.:
0
AF XY:
0.0121
AC XY:
1348
AN XY:
111248
show subpopulations
Gnomad4 AFR exome
AF:
0.0384
Gnomad4 AMR exome
AF:
0.0173
Gnomad4 ASJ exome
AF:
0.0153
Gnomad4 EAS exome
AF:
0.0135
Gnomad4 SAS exome
AF:
0.00902
Gnomad4 FIN exome
AF:
0.00240
Gnomad4 NFE exome
AF:
0.0112
Gnomad4 OTH exome
AF:
0.0151
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0180
AC:
335
AN:
18618
Hom.:
12
Cov.:
4
AF XY:
0.0183
AC XY:
152
AN XY:
8320
show subpopulations
Gnomad4 AFR
AF:
0.0314
Gnomad4 AMR
AF:
0.0266
Gnomad4 ASJ
AF:
0.00602
Gnomad4 EAS
AF:
0.0161
Gnomad4 SAS
AF:
0.0112
Gnomad4 FIN
AF:
0.00289
Gnomad4 NFE
AF:
0.00755
Gnomad4 OTH
AF:
0.0146
Alfa
AF:
0.0124
Hom.:
16
TwinsUK
AF:
0.00890
AC:
33
ALSPAC
AF:
0.0158
AC:
61
ESP6500AA
AF:
0.0168
AC:
74
ESP6500EA
AF:
0.00523
AC:
45
ExAC
AF:
0.0125
AC:
1516

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency Pathogenic:1Benign:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2005- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2025- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalApr 18, 2017BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3% in African population, >1% in most other populations. In addition, no clearly associated clinical manifestations -
Schizophrenia 4 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMMar 01, 2005- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T;.;.;T
Eigen
Uncertain
0.28
Eigen_PC
Benign
0.078
FATHMM_MKL
Benign
0.67
D
LIST_S2
Uncertain
0.89
D;.;D;.
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Benign
-0.53
T
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-7.1
.;D;D;D
REVEL
Benign
0.27
Sift
Pathogenic
0.0
.;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D
Polyphen
0.99
.;D;D;.
Vest4
0.32
MPC
1.1
ClinPred
0.14
T
GERP RS
3.2
gMVP
0.82

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: rs3970559; hg19: chr22-18905899; COSMIC: COSV58230280; COSMIC: COSV58230280; API