Genetic Variant PRODH:p.Asp426Glu (chr22-18918465-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_016335.6(PRODH):c.1278C>A(p.Asp426Glu) 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D426D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 2)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.632

Publications

16 publications found

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]

PRODH Gene-Disease associations (from GenCC):

hyperprolinemia type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	NM_016335.6	MANE Select	c.1278C>A	p.Asp426Glu	missense	Exon 11 of 14	NP_057419.5
PRODH	NM_001195226.2		c.954C>A	p.Asp318Glu	missense	Exon 11 of 14	NP_001182155.2	O43272-2
PRODH	NM_001368250.2		c.954C>A	p.Asp318Glu	missense	Exon 11 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1278C>A	p.Asp426Glu	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
PRODH	ENST00000610940.4	TSL:1	c.1278C>A	p.Asp426Glu	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
PRODH	ENST00000334029.6	TSL:1	c.954C>A	p.Asp318Glu	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

155096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

82772

African (AFR)

AF:

0.00

AC:

AN:

6980

American (AMR)

AF:

0.00

AC:

AN:

7802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5024

East Asian (EAS)

AF:

0.00

AC:

AN:

17318

South Asian (SAS)

AF:

0.00

AC:

AN:

21908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

800

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

79304

Other (OTH)

AF:

0.00

AC:

AN:

9126

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Proline dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

0.22

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.83

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.84

PhyloP100

-0.63

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.51

MutPred

0.58

Loss of catalytic residue at D426 (P = 0.2595)

MVP

0.014

MPC

0.91

ClinPred

0.99

GERP RS

-7.4

gMVP

0.81

Mutation Taster

=53/47

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over