chr22-18913206-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_016335.6(PRODH):c.1772G>A(p.Arg591Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 0)
Exomes 𝑓: 0.0000083 ( 2 hom. )
Failed GnomAD Quality Control
Consequence
PRODH
NM_016335.6 missense
NM_016335.6 missense
Scores
1
13
Clinical Significance
Conservation
PhyloP100: 0.454
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.08200991).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRODH | NM_016335.6 | c.1772G>A | p.Arg591Gln | missense_variant | 14/14 | ENST00000357068.11 | |
PRODH | NM_001195226.2 | c.1448G>A | p.Arg483Gln | missense_variant | 14/14 | ||
PRODH | NM_001368250.2 | c.1448G>A | p.Arg483Gln | missense_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRODH | ENST00000357068.11 | c.1772G>A | p.Arg591Gln | missense_variant | 14/14 | 1 | NM_016335.6 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 0
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GnomAD3 exomes AF: 0.00000638 AC: 1AN: 156628Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 82892
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000834 AC: 4AN: 479450Hom.: 2 Cov.: 0 AF XY: 0.00000849 AC XY: 2AN XY: 235438
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Proline dehydrogenase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 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. ClinVar contains an entry for this variant (Variation ID: 1016144). This variant has not been reported in the literature in individuals affected with PRODH-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 591 of the PRODH protein (p.Arg591Gln). - |
Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 11, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;.;D;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
Sift4G
Benign
T;T;T;T
Polyphen
0.0060
.;B;B;.
Vest4
MVP
MPC
0.32
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at