rs137852934

Variant names:

• chr22-18922389-A-T
• rs137852934
• NM_016335.6:c.865T>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_016335.6(PRODH):​c.865T>A​(p.Leu289Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3 O:1
• Conservation: PhyloP100: 0.567
• Publications: 11 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010837495).
• BP6: Variant 22-18922389-A-T is Benign according to our data. Variant chr22-18922389-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4007.

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.865T>A	p.Leu289Met	missense	Exon 7 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.541T>A	p.Leu181Met	missense	Exon 7 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.541T>A	p.Leu181Met	missense	Exon 7 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.865T>A	p.Leu289Met	missense	Exon 7 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.865T>A	p.Leu289Met	missense	Exon 8 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.541T>A	p.Leu181Met	missense	Exon 7 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00361 AC: 904 AN: 250616 AF XY: 0.00369

Gnomad AFR exome AF: 0.000987

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00728

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00589

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00841 Hom.: 2

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00432 AC: 525

EpiCase AF: 0.00791

EpiControl AF: 0.00488

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	1	Proline dehydrogenase deficiency (3)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)
-	1	-	Schizophrenia 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.15
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.57
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Benign	0.47	T
Polyphen		0.0040	B
Vest4		0.20
MVP		0.081
MPC		0.27
ClinPred		0.0034	T
GERP RS		4.6
gMVP		0.42
Mutation Taster		=80/20	polymorphism

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: rs137852934; hg19: chr22-18909902; COSMIC: COSV99047447; COSMIC: COSV99047447;