rs11913840

Variant names:

• chr22-18925164-C-T
• rs11913840
• NM_016335.6:c.554G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 8P and 8B. PVS1 BP6_Very_Strong

The NM_016335.6(PRODH):​c.554G>A​(p.Trp185*) 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:4
• Conservation: PhyloP100: -0.0560
• Publications: 23 publications found

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]

PRODH Gene-Disease associations (from GenCC):

• hyperprolinemia type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 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 VariationId is 459918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.554G>A	p.Trp185*	stop_gained	Exon 4 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.230G>A	p.Trp77*	stop_gained	Exon 4 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.230G>A	p.Trp77*	stop_gained	Exon 4 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.554G>A	p.Trp185*	stop_gained	Exon 4 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.554G>A	p.Trp185*	stop_gained	Exon 5 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.230G>A	p.Trp77*	stop_gained	Exon 4 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0391 AC: 9822 AN: 251302 AF XY: 0.0378

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 262

American (AMR) AF: 0.00 AC: 0 AN: 1370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 336

East Asian (EAS) AF: 0.00 AC: 0 AN: 1240

South Asian (SAS) AF: 0.00 AC: 0 AN: 5052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 116

European-Non Finnish (NFE) AF: 0.0000707 AC: 1 AN: 14152

Other (OTH) AF: 0.00 AC: 0 AN: 1388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.0414 Hom.: 554

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Proline dehydrogenase deficiency (1)
-	-	1	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.056
Vest4		0.58
GERP RS		-6.1
Mutation Taster		=186/14	polymorphism (auto)

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

Other links and lift over

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