rs4819756

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_016335.6(PRODH):c.553T>C(p.Trp185Arg) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W185Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.83

Publications

48 publications found

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 Gene-Disease associations (from GenCC):

hyperprolinemia type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1503014E-6).

BP6

Variant 22-18925165-A-G is Benign according to our data. Variant chr22-18925165-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.553T>C	p.Trp185Arg	missense_variant	Exon 4 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.229T>C	p.Trp77Arg	missense_variant	Exon 4 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.229T>C	p.Trp77Arg	missense_variant	Exon 4 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.553T>C	p.Trp185Arg	missense_variant	Exon 4 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+14137A>G		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

550

Hom.:

Cov.:

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 NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.638

AC:

160209

AN:

251168

AF XY:

0.634

show subpopulations

Gnomad AFR exome

AF:

0.867

Gnomad AMR exome

AF:

0.622

Gnomad ASJ exome

AF:

0.674

Gnomad EAS exome

AF:

0.967

Gnomad FIN exome

AF:

0.490

Gnomad NFE exome

AF:

0.571

Gnomad OTH exome

AF:

0.620

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000312

AC:

AN:

25616

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

AN XY:

14212

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

256

American (AMR)

AF:

0.00232

AC:

AN:

1294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

320

East Asian (EAS)

AF:

0.00

AC:

AN:

1192

South Asian (SAS)

AF:

0.00

AC:

AN:

4904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

112

European-Non Finnish (NFE)

AF:

0.000364

AC:

AN:

13730

Other (OTH)

AF:

0.00

AC:

AN:

1346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.269

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

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

AF:

0.00

AC:

AN:

550

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

272

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

380

Other (OTH)

AF:

0.00

AC:

AN:

Alfa

AF:

0.605

Hom.:

122042

TwinsUK

AF:

0.553

AC:

2051

ALSPAC

AF:

0.568

AC:

2189

ESP6500AA

AF:

0.862

AC:

3798

ESP6500EA

AF:

0.578

AC:

4967

ExAC

AF:

0.641

AC:

77877

Asia WGS

AF:

0.803

AC:

2793

AN:

3478

EpiCase

AF:

0.593

EpiControl

AF:

0.596

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.039

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

5.3

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0026

T;.;.;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.0069

T;.;T;.;T

MetaRNN

Benign

0.0000012

T;T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

3.8

PrimateAI

Benign

0.25

PROVEAN

Benign

3.7

.;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.50

.;T;T;T;T

Sift4G

Benign

0.53

T;T;T;T;T

Polyphen

0.0

.;B;B;.;.

Vest4

0.033

MutPred

0.32

.;Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);.;.;

MPC

0.48

ClinPred

0.0018

GERP RS

2.9

gMVP

0.36

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over