rs2870984

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PS1_ModerateBP4_StrongBS1_SupportingBS2

The NM_016335.6(PRODH):c.1397C>T(p.Thr466Met) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T466K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 5)

Exomes 𝑓: 0.0048 ( 26 hom. )

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:3O:1

Conservation

PhyloP100: 4.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 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=0.011515439).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00481 (929/193086) while in subpopulation EAS AF= 0.0173 (406/23408). AF 95% confidence interval is 0.016. There are 26 homozygotes in gnomad4_exome. There are 500 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PRODH	NM_016335.6 linkuse as main transcript	c.1397C>T	p.Thr466Met	missense_variant	11/14	ENST00000357068.11
PRODH	NM_001195226.2 linkuse as main transcript	c.1073C>T	p.Thr358Met	missense_variant	11/14
PRODH	NM_001368250.2 linkuse as main transcript	c.1073C>T	p.Thr358Met	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11 linkuse as main transcript	c.1397C>T	p.Thr466Met	missense_variant	11/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

103

AN:

27870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00381

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00943

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00272

GnomAD3 exomes

AF:

0.00463

AC:

1160

AN:

250538

Hom.:

AF XY:

0.00481

AC XY:

651

AN XY:

135446

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00351

Gnomad ASJ exome

AF:

0.00917

Gnomad EAS exome

AF:

0.0144

Gnomad SAS exome

AF:

0.00976

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00253

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00481

AC:

929

AN:

193086

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

500

AN XY:

102144

show subpopulations

Gnomad4 AFR exome

AF:

0.00227

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.0173

Gnomad4 SAS exome

AF:

0.00580

Gnomad4 FIN exome

AF:

0.000718

Gnomad4 NFE exome

AF:

0.00203

Gnomad4 OTH exome

AF:

0.00519

GnomAD4 genome

AF:

0.00372

AC:

104

AN:

27954

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

AN XY:

12788

show subpopulations

Gnomad4 AFR

AF:

0.00363

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.0133

Gnomad4 EAS

AF:

0.0109

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00193

Gnomad4 OTH

AF:

0.00258

Alfa

AF:

0.00292

Hom.:

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00573

AC:

696

EpiCase

AF:

0.00393

EpiControl

AF:

0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Pathogenic:2Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	Intellectual disability; epilepsy; schizophrenia -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PRODH: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	See Variant Classification Assertion Criteria. -

Schizophrenia 4

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;.;D;.

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.72

MutationTaster

Benign

0.97

A;A;A

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

.;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.010

.;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

0.85

.;P;P;.

Vest4

0.45

MVP

0.040

MPC

0.39

ClinPred

0.078

GERP RS

3.1

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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