22-18913491-C-G

Variant names:

• chr22-18913491-C-G
• rs450046
• NM_016335.6:c.1562G>C

Variant summary

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

The NM_016335.6(PRODH):​c.1562G>C​(p.Arg521Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79

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=0.24960318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1562G>C	p.Arg521Pro	missense_variant	Exon 13 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1238G>C	p.Arg413Pro	missense_variant	Exon 13 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.1238G>C	p.Arg413Pro	missense_variant	Exon 13 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1562G>C	p.Arg521Pro	missense_variant	Exon 13 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+2463C>G		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 182310 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 91200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0094	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T;.;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T;.;T;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.83	.;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.10	.;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.018	.;B;B;.
Vest4		0.16
MutPred		0.49		.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.17
MPC		0.50
ClinPred		0.54	D
GERP RS		4.7
gMVP		0.76

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: rs450046; hg19: chr22-18901004;