rs3970559

Positions:

chr22-18918386-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PS1_ModerateBP4_StrongBS1BS2

The NM_016335.6(PRODH):c.1357C>T(p.Arg453Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.018 ( 12 hom., cov: 4)

Exomes 𝑓: 0.013 ( 181 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:3O:1

Conservation

PhyloP100: 2.03

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 Benign. Variant got -10 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=0.012216002).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0125 (2640/211074) while in subpopulation AFR AF= 0.0384 (329/8564). AF 95% confidence interval is 0.035. There are 181 homozygotes in gnomad4_exome. There are 1348 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 181 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6 linkuse as main transcript	c.1357C>T	p.Arg453Cys	missense_variant	11/14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 linkuse as main transcript	c.1033C>T	p.Arg345Cys	missense_variant	11/14		NP_001182155.2	O43272
PRODH	NM_001368250.2 linkuse as main transcript	c.1033C>T	p.Arg345Cys	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 linkuse as main transcript	c.1357C>T	p.Arg453Cys	missense_variant	11/14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 linkuse as main transcript	c.513+7358G>A		intron_variant		5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

332

AN:

18570

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0310

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.00602

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0113

Gnomad FIN

AF:

0.00289

Gnomad MID

AF:

0.0111

Gnomad NFE

AF:

0.00754

Gnomad OTH

AF:

0.0155

GnomAD3 exomes

AF:

0.0108

AC:

2704

AN:

249400

Hom.:

AF XY:

0.0106

AC XY:

1427

AN XY:

134932

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.00737

Gnomad EAS exome

AF:

0.0137

Gnomad SAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.00320

Gnomad NFE exome

AF:

0.00802

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0125

AC:

2640

AN:

211074

Hom.:

181

Cov.:

AF XY:

0.0121

AC XY:

1348

AN XY:

111248

show subpopulations

Gnomad4 AFR exome

AF:

0.0384

Gnomad4 AMR exome

AF:

0.0173

Gnomad4 ASJ exome

AF:

0.0153

Gnomad4 EAS exome

AF:

0.0135

Gnomad4 SAS exome

AF:

0.00902

Gnomad4 FIN exome

AF:

0.00240

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.0151

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0180

AC:

335

AN:

18618

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

152

AN XY:

8320

show subpopulations

Gnomad4 AFR

AF:

0.0314

Gnomad4 AMR

AF:

0.0266

Gnomad4 ASJ

AF:

0.00602

Gnomad4 EAS

AF:

0.0161

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.00289

Gnomad4 NFE

AF:

0.00755

Gnomad4 OTH

AF:

0.0146

Alfa

AF:

0.0124

Hom.:

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.0125

AC:

1516

ClinVar

Significance: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Apr 18, 2017	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3% in African population, >1% in most other populations. In addition, no clearly associated clinical manifestations -

Schizophrenia 4

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.078

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.89

D;.;D;.

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.53

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.1

.;D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Uncertain

0.014

D;D;D;D

Polyphen

0.99

.;D;D;.

Vest4

0.32

MPC

1.1

ClinPred

0.14

GERP RS

3.2

gMVP

0.82

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