rs1807467

Positions:

• chr22-18918380-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PS1_Moderate BP4_Moderate BP6 BS2

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. 13/18 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 0.0012 (1 hom., cov: 4)
  • Exomes 𝑓: 0.0018 (20 hom.)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1 O:1
• Conservation: PhyloP100: 0.182

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 Likely_benign. Variant got -5 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=0.08850092).
• 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 id is 4009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1363G>T	p.Ala455Ser	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1039G>T	p.Ala347Ser	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2	c.1039G>T	p.Ala347Ser	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1363G>T	p.Ala455Ser	missense_variant	11/14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7352C>A		intron_variant		5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 24 AN: 20746 Hom.: 1 Cov.: 4

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

GnomAD3 exomes AF: 0.000941 AC: 236 AN: 250766 Hom.: 1 AF XY: 0.00105 AC XY: 143 AN XY: 135618

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 SAS exome AF: 0.00141

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.: 20 Cov.: 0 AF XY: 0.00175 AC XY: 199 AN XY: 113760

Gnomad4 AFR exome AF: 0.00115

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.000564

Gnomad4 EAS exome AF: 0.00433

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00115 AC: 24 AN: 20796 Hom.: 1 Cov.: 4 AF XY: 0.00107 AC XY: 10 AN XY: 9358

Gnomad4 AFR AF: 0.00114

Gnomad4 AMR AF: 0.000957

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000984

Gnomad4 SAS AF: 0.00149

Gnomad4 FIN AF: 0.000907

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00100 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00133 AC: 162

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Proline dehydrogenase deficiency Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2022	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 455 of the PRODH protein (p.Ala455Ser). This variant is present in population databases (rs1807467, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PRODH-related conditions. ClinVar contains an entry for this variant (Variation ID: 4009). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PRODH function (PMID: 15662599). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2021

The c.1363G>T (p.A455S) alteration is located in exon 12 (coding exon 11) of the PRODH gene. This alteration results from a G to T substitution at nucleotide position 1363, causing the alanine (A) at amino acid position 455 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

PRODH: BP4, BS2 -

Schizophrenia 4 Other:1

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	-0.59	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.024	T;.;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.72	T;.;T;.
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.0	.;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.36	.;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0020	.;B;B;.
Vest4		0.090
MVP		0.014
MPC		0.26
ClinPred		0.0028	T
GERP RS		2.0
gMVP		0.30

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: rs1807467; hg19: chr22-18905893;