chr22-18913492-G-A

Variant names:

• chr22-18913492-G-A
• rs193919334
• NM_016335.6:c.1561C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM5 BP4

The NM_016335.6(PRODH):​c.1561C>T​(p.Arg521Trp) variant causes a missense change. In-silico tool predicts 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: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00014 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.62
• Publications: 3 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 1 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=0.31642967).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.1561C>T	p.Arg521Trp	missense	Exon 13 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1237C>T	p.Arg413Trp	missense	Exon 13 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.1237C>T	p.Arg413Trp	missense	Exon 13 of 14	NP_001355179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1561C>T	p.Arg521Trp	missense	Exon 13 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1561C>T	p.Arg521Trp	missense	Exon 14 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.1237C>T	p.Arg413Trp	missense	Exon 13 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 24758 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 196136 AF XY: 0.0000190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000240

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000137 AC: 25 AN: 182794 Hom.: 12 Cov.: 0 AF XY: 0.000120 AC XY: 11 AN XY: 91422

African (AFR) AF: 0.00 AC: 0 AN: 10520

American (AMR) AF: 0.00 AC: 0 AN: 2858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2266

East Asian (EAS) AF: 0.00 AC: 0 AN: 3002

South Asian (SAS) AF: 0.00 AC: 0 AN: 14114

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1172

European-Non Finnish (NFE) AF: 0.000173 AC: 23 AN: 133188

Other (OTH) AF: 0.000247 AC: 2 AN: 8104

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24758 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12070

African (AFR) AF: 0.00 AC: 0 AN: 11798

American (AMR) AF: 0.00 AC: 0 AN: 1642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 294

East Asian (EAS) AF: 0.00 AC: 0 AN: 410

South Asian (SAS) AF: 0.00 AC: 0 AN: 676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8050

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

ExAC AF: 0.0000251 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.93	T
PhyloP100		3.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.16
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.024	D
Polyphen		0.84	P
Vest4		0.19
MutPred		0.50		Loss of disorder (P = 0.0551)
MVP		0.37
MPC		0.56
ClinPred		0.85	D
GERP RS		3.5
gMVP		0.60
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs193919334; hg19: chr22-18901005;