rs2904552

Positions:

• chr22-18918451-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PS1_Moderate BP4_Strong BA1

The NM_016335.6(PRODH):​c.1292G>A​(p.Arg431His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/17 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 same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.051 (15 hom., cov: 2)
  • Exomes 𝑓: 0.10 (2136 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:2 O:1
• Conservation: PhyloP100: 1.45

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]

ENSG00000283809 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PS1: Transcript NM_016335.6 (PRODH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036971867).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1292G>A	p.Arg431His	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.968G>A	p.Arg323His	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2	c.968G>A	p.Arg323His	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1292G>A	p.Arg431His	missense_variant	11/14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7423C>T		intron_variant		5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 283 AN: 5570 Hom.: 15 Cov.: 2 FAILED QC

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0370

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.0660

GnomAD3 exomes AF: 0.0723 AC: 17881 AN: 247476 Hom.: 837 AF XY: 0.0738 AC XY: 9899 AN XY: 134190

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.000656

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0829

GnomAD4 exome AF: 0.103 AC: 17301 AN: 168500 Hom.: 2136 Cov.: 0 AF XY: 0.0995 AC XY: 8911 AN XY: 89530

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.000642

Gnomad4 SAS exome AF: 0.0519

Gnomad4 FIN exome AF: 0.0682

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0509 AC: 284 AN: 5584 Hom.: 15 Cov.: 2 AF XY: 0.0496 AC XY: 123 AN XY: 2482

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0789

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0271

Gnomad4 FIN AF: 0.0414

Gnomad4 NFE AF: 0.0957

Gnomad4 OTH AF: 0.0625

Alfa AF: 0.0919 Hom.: 282

TwinsUK AF: 0.102 AC: 379

ALSPAC AF: 0.112 AC: 431

ESP6500AA AF: 0.0366 AC: 161

ESP6500EA AF: 0.105 AC: 900

ExAC AF: 0.0746 AC: 9050

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Proline dehydrogenase deficiency Pathogenic:1 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Schizophrenia 4 Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 13, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3, PP3, PP5. -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;.;.;T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;.;D;.
MetaRNN	Benign	0.0037	T;T;T;T
MetaSVM	Benign	-1.2	T
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	.;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0040	.;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D
Polyphen		0.94	.;P;P;.
Vest4		0.16
MPC		0.44
ClinPred		0.033	T
GERP RS		1.2
gMVP		0.62

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

Other links and lift over

dbSNP: rs2904552; hg19: chr22-18905964; COSMIC: COSV58230523; COSMIC: COSV58230523;