22-18913326-T-C

Variant names:

• chr22-18913326-T-C
• rs142346005
• NM_016335.6:c.1652A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_016335.6(PRODH):​c.1652A>G​(p.Tyr551Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic 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. Y551S) has been classified as Likely 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: 3.11
• Publications: 2 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 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-18913326-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522067.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

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.1652A>G	p.Tyr551Cys	missense	Exon 14 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1328A>G	p.Tyr443Cys	missense	Exon 14 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1328A>G	p.Tyr443Cys	missense	Exon 14 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.1652A>G	p.Tyr551Cys	missense	Exon 14 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1652A>G	p.Tyr551Cys	missense	Exon 15 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1328A>G	p.Tyr443Cys	missense	Exon 14 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000571 AC: 1 AN: 175228 AF XY: 0.0000107

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: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 372302 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 186924

African (AFR) AF: 0.00 AC: 0 AN: 16950

American (AMR) AF: 0.00 AC: 0 AN: 13406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7556

East Asian (EAS) AF: 0.00 AC: 0 AN: 10936

South Asian (SAS) AF: 0.00 AC: 0 AN: 24820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 262158

Other (OTH) AF: 0.00 AC: 0 AN: 17392

GnomAD4 genome Cov.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00000846 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.58	T
PhyloP100		3.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.54
MPC		1.1
ClinPred		1.0	D
GERP RS		2.1
gMVP		0.88
Mutation Taster		=45/55	disease causing

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: rs142346005; hg19: chr22-18900839;