dbSNP rs1807467: PRODH:p.Ala455Ser (chr22-18918380-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_016335.6(PRODH):c.1363G>T(p.Ala455Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 4)

Exomes 𝑓: 0.0018 ( 20 hom. )

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.182

Publications

5 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08850092).

BP6

Variant 22-18918380-C-A is Benign according to our data. Variant chr22-18918380-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4009.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00115 (24/20796) while in subpopulation SAS AF = 0.00149 (1/672). AF 95% confidence interval is 0.000783. There are 1 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 4. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	NM_016335.6	MANE Select	c.1363G>T	p.Ala455Ser	missense	Exon 11 of 14	NP_057419.5
PRODH	NM_001195226.2		c.1039G>T	p.Ala347Ser	missense	Exon 11 of 14	NP_001182155.2	O43272-2
PRODH	NM_001368250.2		c.1039G>T	p.Ala347Ser	missense	Exon 11 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1363G>T	p.Ala455Ser	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
PRODH	ENST00000610940.4	TSL:1	c.1363G>T	p.Ala455Ser	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
PRODH	ENST00000334029.6	TSL:1	c.1039G>T	p.Ala347Ser	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

AN:

20746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000961

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000978

Gnomad SAS

AF:

0.00150

Gnomad FIN

AF:

0.000907

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000941

AC:

236

AN:

250766

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00184

AC:

397

AN:

215336

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

199

AN XY:

113760

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

8694

American (AMR)

AF:

0.00131

AC:

AN:

9926

Ashkenazi Jewish (ASJ)

AF:

0.000564

AC:

AN:

7092

East Asian (EAS)

AF:

0.00433

AC:

111

AN:

25614

South Asian (SAS)

AF:

0.00101

AC:

AN:

22856

European-Finnish (FIN)

AF:

0.00162

AC:

AN:

12372

Middle Eastern (MID)

AF:

0.000894

AC:

AN:

1118

European-Non Finnish (NFE)

AF:

0.00173

AC:

198

AN:

114616

Other (OTH)

AF:

0.00130

AC:

AN:

13048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00115

AC:

AN:

20796

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

9358

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

7012

American (AMR)

AF:

0.000957

AC:

AN:

2090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

548

East Asian (EAS)

AF:

0.000984

AC:

AN:

1016

South Asian (SAS)

AF:

0.00149

AC:

AN:

672

European-Finnish (FIN)

AF:

0.000907

AC:

AN:

1102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

7866

Other (OTH)

AF:

0.00

AC:

AN:

294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00100

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00133

AC:

162

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Proline dehydrogenase deficiency (2)

Inborn genetic diseases (1)

not provided (1)

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)

Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.024

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.72

M_CAP

Benign

0.0064

MetaRNN

Benign

0.089

MetaSVM

Benign

-1.0

PhyloP100

0.18

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.0

REVEL

Benign

0.056

Sift

Benign

0.36

Sift4G

Benign

0.56

Polyphen

0.0020

Vest4

0.090

MVP

0.014

MPC

0.26

ClinPred

0.0028

GERP RS

2.0

gMVP

0.30

Mutation Taster

=100/0

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over