rs5992333

Variant names:

• chr22-18916976-G-A
• rs5992333
• NM_016335.6:c.1440C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016335.6(PRODH):​c.1440C>T​(p.Tyr480Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1568 hom., cov: 0)
  • Exomes 𝑓: 0.057 (3950 hom.)
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06
• Publications: 6 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]

PRODH Gene-Disease associations (from GenCC):

• hyperprolinemia type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 22-18916976-G-A is Benign according to our data. Variant chr22-18916976-G-A is described in ClinVar as Benign. ClinVar VariationId is 459912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

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.1440C>T	p.Tyr480Tyr	synonymous	Exon 12 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1116C>T	p.Tyr372Tyr	synonymous	Exon 12 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.1116C>T	p.Tyr372Tyr	synonymous	Exon 12 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.1440C>T	p.Tyr480Tyr	synonymous	Exon 12 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1440C>T	p.Tyr480Tyr	synonymous	Exon 13 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.1116C>T	p.Tyr372Tyr	synonymous	Exon 12 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 3912 AN: 35166 Hom.: 1561 Cov.: 0

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0977

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.00997 AC: 2502 AN: 250904 AF XY: 0.00873

Gnomad AFR exome AF: 0.0579

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0510

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.0575 AC: 8831 AN: 153698 Hom.: 3950 Cov.: 0 AF XY: 0.0550 AC XY: 4344 AN XY: 78924

African (AFR) AF: 0.156 AC: 2384 AN: 15264

American (AMR) AF: 0.112 AC: 477 AN: 4254

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 14 AN: 2230

East Asian (EAS) AF: 0.415 AC: 2707 AN: 6518

South Asian (SAS) AF: 0.0661 AC: 947 AN: 14326

European-Finnish (FIN) AF: 0.000501 AC: 4 AN: 7984

Middle Eastern (MID) AF: 0.102 AC: 113 AN: 1106

European-Non Finnish (NFE) AF: 0.0131 AC: 1227 AN: 93756

Other (OTH) AF: 0.116 AC: 958 AN: 8260

GnomAD4 genome AF: 0.111 AC: 3925 AN: 35274 Hom.: 1568 Cov.: 0 AF XY: 0.111 AC XY: 1880 AN XY: 16876

African (AFR) AF: 0.149 AC: 3106 AN: 20800

American (AMR) AF: 0.0978 AC: 212 AN: 2168

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 8 AN: 316

East Asian (EAS) AF: 0.442 AC: 375 AN: 848

South Asian (SAS) AF: 0.0671 AC: 49 AN: 730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1432

Middle Eastern (MID) AF: 0.128 AC: 10 AN: 78

European-Non Finnish (NFE) AF: 0.0127 AC: 107 AN: 8438

Other (OTH) AF: 0.129 AC: 58 AN: 448

Alfa AF: 0.00831 Hom.: 166

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00243

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Proline dehydrogenase deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.4
DANN	Benign	0.85
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs5992333; hg19: chr22-18904489; COSMIC: COSV58230029; COSMIC: COSV58230029;