rs2904550

Variant names:

• chr22-18918369-G-T
• rs2904550
• NM_016335.6:c.1374C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016335.6(PRODH):​c.1374C>A​(p.Gly458Gly) 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 0.022 (24 hom., cov: 4)
  • Exomes 𝑓: 0.023 (539 hom.)
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.78
• 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=-0.49).
• BP6: Variant 22-18918369-G-T is Benign according to our data. Variant chr22-18918369-G-T is described in ClinVar as [Benign]. Clinvar id is 459911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0216 (492/22792) while in subpopulation SAS AF = 0.0529 (37/700). AF 95% confidence interval is 0.0394. There are 24 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 4. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1374C>A	p.Gly458Gly	synonymous_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1050C>A	p.Gly350Gly	synonymous_variant	Exon 11 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.1050C>A	p.Gly350Gly	synonymous_variant	Exon 11 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1374C>A	p.Gly458Gly	synonymous_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7341G>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 493 AN: 22736 Hom.: 24 Cov.: 4

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.00651

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0195

GnomAD2 exomes AF: 0.0237 AC: 5916 AN: 249230 AF XY: 0.0241

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.0218

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0232 AC: 4947 AN: 212792 Hom.: 539 Cov.: 0 AF XY: 0.0238 AC XY: 2676 AN XY: 112306

African (AFR) AF: 0.0160 AC: 137 AN: 8570

American (AMR) AF: 0.0153 AC: 151 AN: 9866

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 81 AN: 7020

East Asian (EAS) AF: 0.0218 AC: 553 AN: 25376

South Asian (SAS) AF: 0.0373 AC: 845 AN: 22638

European-Finnish (FIN) AF: 0.102 AC: 1265 AN: 12374

Middle Eastern (MID) AF: 0.0160 AC: 18 AN: 1124

European-Non Finnish (NFE) AF: 0.0138 AC: 1562 AN: 112948

Other (OTH) AF: 0.0260 AC: 335 AN: 12876

GnomAD4 genome AF: 0.0216 AC: 492 AN: 22792 Hom.: 24 Cov.: 4 AF XY: 0.0246 AC XY: 254 AN XY: 10322

African (AFR) AF: 0.0151 AC: 117 AN: 7740

American (AMR) AF: 0.0219 AC: 49 AN: 2236

Ashkenazi Jewish (ASJ) AF: 0.00651 AC: 4 AN: 614

East Asian (EAS) AF: 0.0259 AC: 28 AN: 1080

South Asian (SAS) AF: 0.0529 AC: 37 AN: 700

European-Finnish (FIN) AF: 0.0993 AC: 119 AN: 1198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.0149 AC: 130 AN: 8700

Other (OTH) AF: 0.0155 AC: 5 AN: 322

Alfa AF: 0.0186 Hom.: 30

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.0235

EpiControl AF: 0.0178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Proline dehydrogenase deficiency Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.0
DANN	Benign	0.82
PhyloP100		2.8
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2904550; hg19: chr22-18905882; COSMIC: COSV100471760; COSMIC: COSV100471760;