rs2238731
Positions:
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_ModerateBP4_StrongBP6_Very_StrongBA1
The NM_016335.6(PRODH):c.1279G>A(p.Val427Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Genomes: 𝑓 0.030 ( 4 hom., cov: 2)
Exomes 𝑓: 0.036 ( 394 hom. )
Failed GnomAD Quality Control
Consequence
PRODH
NM_016335.6 missense
NM_016335.6 missense
Scores
1
12
Clinical Significance
Conservation
PhyloP100: 0.286
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 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=0.0030622482).
BP6
?
Variant 22-18918464-C-T is Benign according to our data. Variant chr22-18918464-C-T is described in ClinVar as [Benign]. Clinvar id is 459909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
?
GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0996 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRODH | NM_016335.6 | c.1279G>A | p.Val427Met | missense_variant | 11/14 | ENST00000357068.11 | |
PRODH | NM_001195226.2 | c.955G>A | p.Val319Met | missense_variant | 11/14 | ||
PRODH | NM_001368250.2 | c.955G>A | p.Val319Met | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRODH | ENST00000357068.11 | c.1279G>A | p.Val427Met | missense_variant | 11/14 | 1 | NM_016335.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 120AN: 3904Hom.: 4 Cov.: 2 FAILED QC
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GnomAD3 exomes AF: 0.0384 AC: 9422AN: 245360Hom.: 395 AF XY: 0.0330 AC XY: 4391AN XY: 133088
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GnomAD4 exome AF: 0.0357 AC: 5726AN: 160352Hom.: 394 Cov.: 0 AF XY: 0.0331 AC XY: 2826AN XY: 85352
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0302 AC: 118AN: 3912Hom.: 4 Cov.: 2 AF XY: 0.0329 AC XY: 59AN XY: 1796
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2019 | This variant is associated with the following publications: (PMID: 23462603, 15662599, 24842239, 22090377) - |
Proline dehydrogenase deficiency Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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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;.
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
P;P;P
PrimateAI
Benign
T
Sift4G
Benign
T;T;T;T
Polyphen
0.35
.;B;B;.
Vest4
MPC
0.30
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