NM_016335.6:c.1772G>A

Variant names:

• chr22-18913206-C-T
• rs779412444
• NM_016335.6:c.1772G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016335.6(PRODH):​c.1772G>A​(p.Arg591Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000083 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.454

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08200991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1772G>A	p.Arg591Gln	missense_variant	Exon 14 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1448G>A	p.Arg483Gln	missense_variant	Exon 14 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.1448G>A	p.Arg483Gln	missense_variant	Exon 14 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1772G>A	p.Arg591Gln	missense_variant	Exon 14 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+2178C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000638 AC: 1 AN: 156628 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82892

Gnomad AFR exome AF: 0.000114

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: AS_VQSR AF: 0.00000834 AC: 4 AN: 479450 Hom.: 2 Cov.: 0 AF XY: 0.00000849 AC XY: 2 AN XY: 235438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000182

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000553

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000349 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proline dehydrogenase deficiency Uncertain:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 591 of the PRODH protein (p.Arg591Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1016144). This variant has not been reported in the literature in individuals affected with PRODH-related conditions. -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 Uncertain:1

Feb 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.015	T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.097	N
LIST_S2	Uncertain	0.93	D;.;D;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.87	.;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.31	.;T;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.0060	.;B;B;.
Vest4		0.069
MVP		0.030
MPC		0.32
ClinPred		0.042	T
GERP RS		-3.5
gMVP		0.35

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: rs779412444; hg19: chr22-18900719;