22-18918329-C-T

Position:

• chr22-18918329-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_Moderate BP4_Strong BP6_Very_Strong BA1

The ENST00000357068.11(PRODH):​c.1414G>A​(p.Ala472Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.055 (108 hom., cov: 5)
  • Exomes 𝑓: 0.061 (746 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH ENST00000357068.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.110

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PS1: Transcript ENST00000357068.11 (PRODH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017911196).
• BP6: Variant 22-18918329-C-T is Benign according to our data. Variant chr22-18918329-C-T is described in ClinVar as [Benign]. Clinvar id is 1168804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1414G>A	p.Ala472Thr	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1090G>A	p.Ala364Thr	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2	c.1090G>A	p.Ala364Thr	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1414G>A	p.Ala472Thr	missense_variant	11/14	1	NM_016335.6	ENSP00000349577	P3

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 1661 AN: 30174 Hom.: 109 Cov.: 5

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0236

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.0760

Gnomad OTH AF: 0.0676

GnomAD3 exomes AF: 0.0494 AC: 12348 AN: 250070 Hom.: 402 AF XY: 0.0491 AC XY: 6641 AN XY: 135236

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.0480

Gnomad ASJ exome AF: 0.0693

Gnomad EAS exome AF: 0.0233

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.0558

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0610 AC: 8552 AN: 140242 Hom.: 746 Cov.: 0 AF XY: 0.0605 AC XY: 4473 AN XY: 73976

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.0832

Gnomad4 EAS exome AF: 0.0319

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.0746

Gnomad4 NFE exome AF: 0.0736

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0549 AC: 1661 AN: 30272 Hom.: 108 Cov.: 5 AF XY: 0.0547 AC XY: 763 AN XY: 13942

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.0617

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0237

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.0752

Gnomad4 NFE AF: 0.0760

Gnomad4 OTH AF: 0.0628

Alfa AF: 0.0521 Hom.: 197

TwinsUK AF: 0.0434 AC: 161

ALSPAC AF: 0.0441 AC: 170

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.0601 AC: 517

ExAC AF: 0.0504 AC: 6120

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	This variant is associated with the following publications: (PMID: 22090377, 15662599, 23462603) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Proline dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.3
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T;.;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.39	T;.;T;.
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.91	.;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.52	.;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.010	.;B;B;.
Vest4		0.091
MPC		0.27
ClinPred		0.0067	T
GERP RS		0.86
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2870983; hg19: chr22-18905842; COSMIC: COSV58230172; COSMIC: COSV58230172;