Variant 22-18925068-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_016335.6(PRODH):c.650G>A(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.092 ( 11 hom., cov: 0)

Exomes 𝑓: 0.11 ( 1681 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0210

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011050582).

BP6

Variant 22-18925068-C-T is Benign according to our data. Variant chr22-18925068-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547846.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.650G>A	p.Arg217His	missense_variant	4/14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.326G>A	p.Arg109His	missense_variant	4/14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.326G>A	p.Arg109His	missense_variant	4/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.650G>A	p.Arg217His	missense_variant	4/14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+14040C>T		intron_variant		5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

282

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMR

AF:

0.0714

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00472

AC:

1185

AN:

251136

Hom.:

AF XY:

0.00462

AC XY:

628

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.00659

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.112

AC:

3477

AN:

31000

Hom.:

1681

Cov.:

AF XY:

0.105

AC XY:

1793

AN XY:

16996

show subpopulations

Gnomad4 AFR exome

AF:

0.0359

Gnomad4 AMR exome

AF:

0.0203

Gnomad4 ASJ exome

AF:

0.0417

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0438

Gnomad4 FIN exome

AF:

0.156

Gnomad4 NFE exome

AF:

0.150

Gnomad4 OTH exome

AF:

0.0980

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0922

AC:

AN:

282

Hom.:

Cov.:

AF XY:

0.0846

AC XY:

AN XY:

130

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0714

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.150

Gnomad4 NFE

AF:

0.104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00622

Hom.:

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00445

AC:

540

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PRODH: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.024

T;.;.;T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.077

LIST_S2

Uncertain

0.88

D;.;T;.;T

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

.;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.12

.;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.0060

.;B;B;.;.

Vest4

0.052

MVP

0.14

MPC

0.34

ClinPred

0.010

GERP RS

-2.2

gMVP

0.29

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