Genetic Variant NM_016335.6:c.1006G>A (chr22-18921347-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016335.6(PRODH):c.1006G>A(p.Ala336Thr) 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)

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.234

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 links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03703481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1006G>A	p.Ala336Thr	missense_variant	Exon 8 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.682G>A	p.Ala228Thr	missense_variant	Exon 8 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.682G>A	p.Ala228Thr	missense_variant	Exon 8 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.1006G>A	p.Ala336Thr	missense_variant	Exon 8 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+10319C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

160816

Hom.:

AF XY:

0.0000236

AC XY:

AN XY:

84726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000317

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000530

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Uncertain:1

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Proline dehydrogenase deficiency

Uncertain:1

Sep 14, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 336 of the PRODH protein (p.Ala336Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PRODH-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.0

DANN

Benign

0.87

DEOGEN2

Benign

0.0056

T;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.71

T;.;T;.

M_CAP

Benign

0.0029

MetaRNN

Benign

0.037

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.35

.;N;N;N

REVEL

Benign

0.067

Sift

Benign

0.62

.;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.028

MutPred

0.53

Gain of sheet (P = 0.0344);.;.;Gain of sheet (P = 0.0344);

MVP

0.030

MPC

0.27

ClinPred

0.026

GERP RS

-5.1

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over