dbSNP rs2904550: PRODH:p.Gly458Gly (chr22-18918369-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_016335.6(PRODH):c.1374C>A(p.Gly458Gly) 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 0.022 ( 24 hom., cov: 4)

Exomes 𝑓: 0.023 ( 539 hom. )

Consequence

PRODH
NM_016335.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.78

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=-0.49).

BP6

Variant 22-18918369-G-T is Benign according to our data. Variant chr22-18918369-G-T is described in ClinVar as [Benign]. Clinvar id is 459911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.78 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0216 (492/22792) while in subpopulation SAS AF= 0.0529 (37/700). AF 95% confidence interval is 0.0394. There are 24 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 4. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1374C>A	p.Gly458Gly	synonymous_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1050C>A	p.Gly350Gly	synonymous_variant	Exon 11 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1050C>A	p.Gly350Gly	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.1374C>A	p.Gly458Gly	synonymous_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+7341G>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

493

AN:

22736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.00651

Gnomad EAS

AF:

0.0267

Gnomad SAS

AF:

0.0533

Gnomad FIN

AF:

0.0993

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0195

GnomAD3 exomes

AF:

0.0237

AC:

5916

AN:

249230

Hom.:

132

AF XY:

0.0241

AC XY:

3251

AN XY:

134802

show subpopulations

Gnomad AFR exome

AF:

0.0180

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.00609

Gnomad EAS exome

AF:

0.0218

Gnomad SAS exome

AF:

0.0387

Gnomad FIN exome

AF:

0.0528

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0232

AC:

4947

AN:

212792

Hom.:

539

Cov.:

AF XY:

0.0238

AC XY:

2676

AN XY:

112306

show subpopulations

Gnomad4 AFR exome

AF:

0.0160

Gnomad4 AMR exome

AF:

0.0153

Gnomad4 ASJ exome

AF:

0.0115

Gnomad4 EAS exome

AF:

0.0218

Gnomad4 SAS exome

AF:

0.0373

Gnomad4 FIN exome

AF:

0.102

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.0260

GnomAD4 genome

AF:

0.0216

AC:

492

AN:

22792

Hom.:

Cov.:

AF XY:

0.0246

AC XY:

254

AN XY:

10322

show subpopulations

Gnomad4 AFR

AF:

0.0151

Gnomad4 AMR

AF:

0.0219

Gnomad4 ASJ

AF:

0.00651

Gnomad4 EAS

AF:

0.0259

Gnomad4 SAS

AF:

0.0529

Gnomad4 FIN

AF:

0.0993

Gnomad4 NFE

AF:

0.0149

Gnomad4 OTH

AF:

0.0155

Alfa

AF:

0.0186

Hom.:

Asia WGS

AF:

0.0400

AC:

138

AN:

3478

EpiCase

AF:

0.0235

EpiControl

AF:

0.0178

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

-0.49

CADD

Benign

5.0

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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