22-18913318-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_016335.6(PRODH):c.1660G>A(p.Val554Met) 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: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000042 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.63

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:

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]

DGCR6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1660G>A	p.Val554Met	missense_variant	Exon 14 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1336G>A	p.Val446Met	missense_variant	Exon 14 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1336G>A	p.Val446Met	missense_variant	Exon 14 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.1660G>A	p.Val554Met	missense_variant	Exon 14 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+2290C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

29852

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000172

AC:

AN:

174342

Hom.:

AF XY:

0.0000107

AC XY:

AN XY:

93146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000374

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:

0.0000283

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000417

AC:

AN:

383938

Hom.:

Cov.:

AF XY:

0.0000518

AC XY:

AN XY:

192972

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000802

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000515

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

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

AF:

0.00

AC:

AN:

29852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

14374

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1660G>A (p.V554M) alteration is located in exon 15 (coding exon 14) of the PRODH gene. This alteration results from a G to A substitution at nucleotide position 1660, causing the valine (V) at amino acid position 554 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Proline dehydrogenase deficiency

Uncertain:1

Apr 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 554 of the PRODH protein (p.Val554Met). 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 variant has not been reported in the literature in individuals affected with PRODH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;.;D;.

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Benign

-0.52

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

.;D;D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.58

MVP

0.32

MPC

0.93

ClinPred

0.90

GERP RS

4.4

gMVP

0.66

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