rs450046

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-18913491-C-T
• chr22-18913491-C-A
• chr22-18913491-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM5 BP4_Strong BP6_Very_Strong

The NM_016335.6(PRODH):​c.1562G>A​(p.Arg521Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0050 (458 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -10 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=2.6020018E-5).
• BP6: Variant 22-18913491-C-T is Benign according to our data. Variant chr22-18913491-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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>A	p.Arg521Gln	missense	Exon 13 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1238G>A	p.Arg413Gln	missense	Exon 13 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1238G>A	p.Arg413Gln	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>A	p.Arg521Gln	missense	Exon 13 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1562G>A	p.Arg521Gln	missense	Exon 14 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1238G>A	p.Arg413Gln	missense	Exon 13 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 63 AN: 23476 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.928 AC: 185101 AN: 199402 AF XY: 0.928

Gnomad AFR exome AF: 0.816

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.953

Gnomad EAS exome AF: 0.958

Gnomad FIN exome AF: 0.916

Gnomad NFE exome AF: 0.932

Gnomad OTH exome AF: 0.931

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00504 AC: 919 AN: 182174 Hom.: 458 Cov.: 0 AF XY: 0.00526 AC XY: 479 AN XY: 91130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0362 AC: 368 AN: 10168

American (AMR) AF: 0.0277 AC: 78 AN: 2820

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 6 AN: 2262

East Asian (EAS) AF: 0.0525 AC: 154 AN: 2936

South Asian (SAS) AF: 0.0118 AC: 166 AN: 14078

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

Middle Eastern (MID) AF: 0.00686 AC: 8 AN: 1166

European-Non Finnish (NFE) AF: 0.000421 AC: 56 AN: 133156

Other (OTH) AF: 0.0104 AC: 83 AN: 8018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00268 AC: 63 AN: 23546 Hom.: 0 Cov.: 0 AF XY: 0.00304 AC XY: 35 AN XY: 11498

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00572 AC: 61 AN: 10656

American (AMR) AF: 0.00 AC: 0 AN: 1610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 290

East Asian (EAS) AF: 0.00250 AC: 1 AN: 400

South Asian (SAS) AF: 0.00148 AC: 1 AN: 676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8032

Other (OTH) AF: 0.00 AC: 0 AN: 286

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.915 Hom.: 268204

TwinsUK AF: 0.934 AC: 3465

ALSPAC AF: 0.934 AC: 3598

ESP6500AA AF: 0.836 AC: 3678

ESP6500EA AF: 0.939 AC: 8073

ExAC AF: 0.915 AC: 107769

Asia WGS AF: 0.912 AC: 3172 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Proline dehydrogenase deficiency (2)
-	-	1	not provided (1)
-	-	1	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.000026	T
MetaSVM	Benign	-0.98	T
PhyloP100		3.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.055
Sift	Benign	0.46	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.32
ClinPred		0.025	T
GERP RS		4.7
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV58230786; COSMIC: COSV58230786;