22-18913491-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_016335.6(PRODH):c.1562G>A(p.Arg521Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0050 ( 458 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.79

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.6020018E-5).

BP6

Variant 22-18913491-C-T is Benign according to our data. Variant chr22-18913491-C-T is described in ClinVar as [Benign]. Clinvar id is 1168803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18913491-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00268 (63/23546) while in subpopulation AFR AF= 0.00572 (61/10656). AF 95% confidence interval is 0.00457. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1562G>A	p.Arg521Gln	missense_variant	Exon 13 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1238G>A	p.Arg413Gln	missense_variant	Exon 13 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1238G>A	p.Arg413Gln	missense_variant	Exon 13 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.1562G>A	p.Arg521Gln	missense_variant	Exon 13 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+2463C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

AN:

23476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00576

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.00148

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.928

AC:

185101

AN:

199402

Hom.:

86047

AF XY:

0.928

AC XY:

99243

AN XY:

106952

show subpopulations

Gnomad AFR exome

AF:

0.816

Gnomad AMR exome

AF:

0.965

Gnomad ASJ exome

AF:

0.953

Gnomad EAS exome

AF:

0.958

Gnomad SAS exome

AF:

0.909

Gnomad FIN exome

AF:

0.916

Gnomad NFE exome

AF:

0.932

Gnomad OTH exome

AF:

0.931

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00504

AC:

919

AN:

182174

Hom.:

458

Cov.:

AF XY:

0.00526

AC XY:

479

AN XY:

91130

show subpopulations

Gnomad4 AFR exome

AF:

0.0362

Gnomad4 AMR exome

AF:

0.0277

Gnomad4 ASJ exome

AF:

0.00265

Gnomad4 EAS exome

AF:

0.0525

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000421

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.00268

AC:

AN:

23546

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

AN XY:

11498

show subpopulations

Gnomad4 AFR

AF:

0.00572

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00250

Gnomad4 SAS

AF:

0.00148

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.906

Hom.:

152163

TwinsUK

AF:

0.934

AC:

3465

ALSPAC

AF:

0.934

AC:

3598

ESP6500AA

AF:

0.836

AC:

3678

ESP6500EA

AF:

0.939

AC:

8073

ExAC

AF:

0.915

AC:

107769

Asia WGS

AF:

0.912

AC:

3172

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Benign:1

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.0088

T;.;.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.17

T;.;T;.

MetaRNN

Benign

0.000026

T;T;T;T

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.48

PROVEAN

Benign

0.77

.;N;N;N

REVEL

Benign

0.055

Sift

Benign

0.46

.;T;T;T

Sift4G

Benign

0.38

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.030

MPC

0.32

ClinPred

0.025

GERP RS

4.7

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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