22-18918325-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_016335.6(PRODH):c.1418T>C(p.Met473Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 5)

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: 5.63

Publications

0 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: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

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
PRODH	NM_016335.6	MANE Select	c.1418T>C	p.Met473Thr	missense	Exon 11 of 14	NP_057419.5
PRODH	NM_001195226.2		c.1094T>C	p.Met365Thr	missense	Exon 11 of 14	NP_001182155.2
PRODH	NM_001368250.2		c.1094T>C	p.Met365Thr	missense	Exon 11 of 14	NP_001355179.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1418T>C	p.Met473Thr	missense	Exon 11 of 14	ENSP00000349577.6
PRODH	ENST00000610940.4	TSL:1	c.1418T>C	p.Met473Thr	missense	Exon 12 of 15	ENSP00000480347.1
PRODH	ENST00000334029.6	TSL:1	c.1094T>C	p.Met365Thr	missense	Exon 11 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

136254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71906

African (AFR)

AF:

0.00

AC:

AN:

6130

American (AMR)

AF:

0.00

AC:

AN:

6354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4492

East Asian (EAS)

AF:

0.00

AC:

AN:

17966

South Asian (SAS)

AF:

0.00

AC:

AN:

13338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

70976

Other (OTH)

AF:

0.00

AC:

AN:

8250

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Uncertain:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 529418). 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. This variant has not been reported in the literature in individuals affected with PRODH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 473 of the PRODH protein (p.Met473Thr).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.075

Eigen

Benign

-0.035

Eigen_PC

Benign

0.028

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-1.0

PhyloP100

5.6

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.29

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.63

Vest4

0.71

MutPred

0.75

Loss of stability (P = 0.0636)

MVP

0.055

MPC

0.42

ClinPred

0.91

GERP RS

4.2

gMVP

0.78

Mutation Taster

=11/89

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over