Genetic Variant PRODH:p.Ala454Ala (chr22-18918381-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016335.6(PRODH):c.1362G>A(p.Ala454Ala) variant causes a synonymous 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 Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 18 hom., cov: 4)

Exomes 𝑓: 0.014 ( 215 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -7.07

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 22-18918381-C-T is Benign according to our data. Variant chr22-18918381-C-T is described in ClinVar as [Benign]. Clinvar id is 459910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.07 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1362G>A	p.Ala454Ala	synonymous_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1038G>A	p.Ala346Ala	synonymous_variant	Exon 11 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1038G>A	p.Ala346Ala	synonymous_variant	Exon 11 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.1362G>A	p.Ala454Ala	synonymous_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+7353C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

534

AN:

19278

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0590

Gnomad AMI

AF:

0.0870

Gnomad AMR

AF:

0.0326

Gnomad ASJ

AF:

0.00579

Gnomad EAS

AF:

0.0103

Gnomad SAS

AF:

0.0125

Gnomad FIN

AF:

0.00187

Gnomad MID

AF:

0.0109

Gnomad NFE

AF:

0.00778

Gnomad OTH

AF:

0.0229

GnomAD3 exomes

AF:

0.0142

AC:

3550

AN:

249354

Hom.:

AF XY:

0.0131

AC XY:

1773

AN XY:

134910

show subpopulations

Gnomad AFR exome

AF:

0.0620

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.00588

Gnomad EAS exome

AF:

0.0133

Gnomad SAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.00769

Gnomad NFE exome

AF:

0.00975

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0144

AC:

3047

AN:

211424

Hom.:

215

Cov.:

AF XY:

0.0138

AC XY:

1543

AN XY:

111674

show subpopulations

Gnomad4 AFR exome

AF:

0.0693

Gnomad4 AMR exome

AF:

0.0198

Gnomad4 ASJ exome

AF:

0.0127

Gnomad4 EAS exome

AF:

0.0135

Gnomad4 SAS exome

AF:

0.0110

Gnomad4 FIN exome

AF:

0.00364

Gnomad4 NFE exome

AF:

0.0114

Gnomad4 OTH exome

AF:

0.0184

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0279

AC:

539

AN:

19328

Hom.:

Cov.:

AF XY:

0.0272

AC XY:

236

AN XY:

8662

show subpopulations

Gnomad4 AFR

AF:

0.0594

Gnomad4 AMR

AF:

0.0325

Gnomad4 ASJ

AF:

0.00579

Gnomad4 EAS

AF:

0.0104

Gnomad4 SAS

AF:

0.0125

Gnomad4 FIN

AF:

0.00187

Gnomad4 NFE

AF:

0.00779

Gnomad4 OTH

AF:

0.0216

Alfa

AF:

0.0175

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Proline dehydrogenase deficiency

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.0

DANN

Benign

0.94

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