22-18913491-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5 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. 14/20 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. R521G) has been classified as Pathogenic.

• 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
• Publications: 55 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]

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-18913492-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4012.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24960318).

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.1562G>C	p.Arg521Pro	missense	Exon 13 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1238G>C	p.Arg413Pro	missense	Exon 13 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1238G>C	p.Arg413Pro	missense	Exon 13 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.1562G>C	p.Arg521Pro	missense	Exon 13 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1562G>C	p.Arg521Pro	missense	Exon 14 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1238G>C	p.Arg413Pro	missense	Exon 13 of 14	ENSP00000334726.2	O43272-2

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

African (AFR) AF: 0.00 AC: 0 AN: 10252

American (AMR) AF: 0.00 AC: 0 AN: 2824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2264

East Asian (EAS) AF: 0.00 AC: 0 AN: 2944

South Asian (SAS) AF: 0.00 AC: 0 AN: 14082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1168

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 133162

Other (OTH) AF: 0.00 AC: 0 AN: 8044

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0094	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.24
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.018	B
Vest4		0.16
MutPred		0.49		Loss of sheet (P = 0.0817)
MVP		0.17
MPC		0.50
ClinPred		0.54	D
GERP RS		4.7
gMVP		0.76
Mutation Taster		=51/49	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: rs450046; hg19: chr22-18901004;