rs2238731

Positions:

• chr22-18918464-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 NM_016335.6(PRODH):​c.1279G>A​(p.Val427Met) 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 0.030 (4 hom., cov: 2)
  • Exomes 𝑓: 0.036 (394 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.286

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 -18 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=0.0030622482).
• BP6: Variant 22-18918464-C-T is Benign according to our data. Variant chr22-18918464-C-T is described in ClinVar as [Benign]. Clinvar id is 459909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0996 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1279G>A	p.Val427Met	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.955G>A	p.Val319Met	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2	c.955G>A	p.Val319Met	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1279G>A	p.Val427Met	missense_variant	11/14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7436C>T		intron_variant		5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 120 AN: 3904 Hom.: 4 Cov.: 2 FAILED QC

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.00385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0109

GnomAD3 exomes AF: 0.0384 AC: 9422 AN: 245360 Hom.: 395 AF XY: 0.0330 AC XY: 4391 AN XY: 133088

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00295

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0357 AC: 5726 AN: 160352 Hom.: 394 Cov.: 0 AF XY: 0.0331 AC XY: 2826 AN XY: 85352

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.0904

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00501

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0378

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0302 AC: 118 AN: 3912 Hom.: 4 Cov.: 2 AF XY: 0.0329 AC XY: 59 AN XY: 1796

Gnomad4 AFR AF: 0.0412

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0872

Gnomad4 SAS AF: 0.00382

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0211 Hom.: 34

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.0795 AC: 350

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.0362 AC: 4393

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: 23462603, 15662599, 24842239, 22090377) -
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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0068	T;.;.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.90	D;.;D;.
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.56	.;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.50	.;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.35	.;B;B;.
Vest4		0.074
MPC		0.30
ClinPred		0.0020	T
GERP RS		-1.1
gMVP		0.59

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: rs2238731; hg19: chr22-18905977; COSMIC: COSV58230771; COSMIC: COSV58230771;