rs772562722

Variant names:

• chr22-18919466-G-T
• rs772562722
• NM_016335.6:c.1236C>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_016335.6(PRODH):​c.1236C>A​(p.Tyr412*) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 3)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.11
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-18919466-G-T is Pathogenic according to our data. Variant chr22-18919466-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521785.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.1236C>A	p.Tyr412*	stop_gained	Exon 10 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.912C>A	p.Tyr304*	stop_gained	Exon 10 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.912C>A	p.Tyr304*	stop_gained	Exon 10 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.1236C>A	p.Tyr412*	stop_gained	Exon 10 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1236C>A	p.Tyr412*	stop_gained	Exon 11 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.912C>A	p.Tyr304*	stop_gained	Exon 10 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250716 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 31146 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 15614

African (AFR) AF: 0.00 AC: 0 AN: 1324

American (AMR) AF: 0.00 AC: 0 AN: 910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1352

East Asian (EAS) AF: 0.00 AC: 0 AN: 7248

South Asian (SAS) AF: 0.00 AC: 0 AN: 562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 15558

Other (OTH) AF: 0.00 AC: 0 AN: 2044

GnomAD4 genome Cov.: 3

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Proline dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.0085
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.1
Vest4		0.87
GERP RS		1.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772562722; hg19: chr22-18906979;