22-18913333-C-T

Variant names:

• chr22-18913333-C-T
• rs1321845990
• NM_016335.6:c.1645G>A

Variant summary

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

The NM_016335.6(PRODH):​c.1645G>A​(p.Val549Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1645G>A	p.Val549Met	missense_variant	Exon 14 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1321G>A	p.Val441Met	missense_variant	Exon 14 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.1321G>A	p.Val441Met	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.1645G>A	p.Val549Met	missense_variant	Exon 14 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+2305C>T		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: 362746 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 182038

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 11, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1645G>A (p.V549M) alteration is located in exon 15 (coding exon 14) of the PRODH gene. This alteration results from a G to A substitution at nucleotide position 1645, causing the valine (V) at amino acid position 549 to be replaced by a methionine (M). The p.V549M alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;.;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T;.;D;.
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	.;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.030	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	.;D;D;.
Vest4		0.19
MutPred		0.68		Gain of catalytic residue at V545 (P = 0.0394);.;.;Gain of catalytic residue at V545 (P = 0.0394);
MVP		0.24
MPC		0.63
ClinPred		0.96	D
GERP RS		2.3
gMVP		0.73

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: rs1321845990; hg19: chr22-18900846; COSMIC: COSV104396028; COSMIC: COSV104396028;