22-18913492-G-C

Position:

• chr22-18913492-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_016335.6(PRODH):​c.1561C>G​(p.Arg521Gly) variant causes a missense change. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.62

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:):

DGCR6 (HGNC:2846): (DiGeorge syndrome critical region gene 6) DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 22-18913492-G-C is Pathogenic according to our data. Variant chr22-18913492-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4012.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1561C>G	p.Arg521Gly	missense_variant	13/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1237C>G	p.Arg413Gly	missense_variant	13/14		NP_001182155.2
PRODH	NM_001368250.2	c.1237C>G	p.Arg413Gly	missense_variant	13/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1561C>G	p.Arg521Gly	missense_variant	13/14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+2464G>C		intron_variant		5		ENSP00000492446.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Proline dehydrogenase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.029	T;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.47	T;.;T;.
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.084	.;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.0040	.;B;B;.
Vest4		0.12
MutPred		0.44		.;Gain of catalytic residue at V414 (P = 0.0782);Gain of catalytic residue at V414 (P = 0.0782);.;
MVP		0.25
MPC		0.37
ClinPred		0.41	T
GERP RS		3.5
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs193919334; hg19: chr22-18901005;