rs11913840

chr22-18925164-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 8P and 12B. PVS1 BP6_Very_Strong BS2

The NM_016335.6(PRODH):c.554G>A(p.Trp185Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0560

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 Likely_benign. Variant got -4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 22-18925164-C-T is Benign according to our data. Variant chr22-18925164-C-T is described in ClinVar as [Benign]. Clinvar id is 459918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18925164-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 272 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.554G>A	p.Trp185Ter	stop_gained	4/14	ENST00000357068.11
PRODH	NM_001195226.2	c.230G>A	p.Trp77Ter	stop_gained	4/14
PRODH	NM_001368250.2	c.230G>A	p.Trp77Ter	stop_gained	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.554G>A	p.Trp185Ter	stop_gained	4/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0391 AC: 9822 AN: 251302 Hom.: 272 AF XY: 0.0378 AC XY: 5141 AN XY: 135878

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.0296

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.0375

Gnomad OTH exome AF: 0.0530

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000378 AC: 1 AN: 26422 Hom.: 0 Cov.: 0 AF XY: 0.0000683 AC XY: 1 AN XY: 14652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000707

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.0403 Hom.: 223

TwinsUK AF: 0.0380 AC: 141

ALSPAC AF: 0.0363 AC: 140

ESP6500AA AF: 0.101 AC: 445

ESP6500EA AF: 0.0364 AC: 313

ExAC AF: 0.0399 AC: 4849

Asia WGS AF: 0.0450 AC: 155 AN: 3478

EpiCase AF: 0.0432

EpiControl AF: 0.0412

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 Benign:1

Benign, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Benign	0.89
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.050	N
MutationTaster	Benign	1.5e-18	P;P;P
Vest4		0.58
GERP RS		-6.1

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: rs11913840; hg19: chr22-18912677; COSMIC: COSV58230362; COSMIC: COSV58230362;