22-18922389-A-T

Position:

• chr22-18922389-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PS1_Moderate BP4_Strong BP6

The NM_016335.6(PRODH):​c.865T>A​(p.Leu289Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 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: not found (cov: 0)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3 O:1
• Conservation: PhyloP100: 0.567

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 -3 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=0.010837495).
• BP6: Variant 22-18922389-A-T is Benign according to our data. Variant chr22-18922389-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.865T>A	p.Leu289Met	missense_variant	7/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.541T>A	p.Leu181Met	missense_variant	7/14		NP_001182155.2
PRODH	NM_001368250.2	c.541T>A	p.Leu181Met	missense_variant	7/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.865T>A	p.Leu289Met	missense_variant	7/14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+11361A>T		intron_variant		5		ENSP00000492446.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00361 AC: 904 AN: 250616 Hom.: 5 AF XY: 0.00369 AC XY: 500 AN XY: 135494

Gnomad AFR exome AF: 0.000987

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00728

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00589

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00841 Hom.: 2

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00432 AC: 525

EpiCase AF: 0.00791

EpiControl AF: 0.00488

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Schizophrenia 4 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 27, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18506409, 28202261, 12217952, 15662599, 24498354, 15494707) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.15
DEOGEN2	Benign	0.0069	T;.;.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.13	T;.;T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.060	.;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.48	.;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0040	.;B;B;.;.
Vest4		0.20
MVP		0.081
MPC		0.27
ClinPred		0.0034	T
GERP RS		4.6
gMVP		0.42

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: rs137852934; hg19: chr22-18909902; COSMIC: COSV99047447; COSMIC: COSV99047447;