22-18913355-G-C

Variant names:

• chr22-18913355-G-C
• rs16983347
• NM_016335.6:c.1623C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_016335.6(PRODH):​c.1623C>G​(p.Ala541Ala) 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A541A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.85
• 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]

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 22-18913355-G-C is Benign according to our data. Variant chr22-18913355-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.85 with no splicing effect.

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.1623C>G	p.Ala541Ala	synonymous	Exon 14 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1299C>G	p.Ala433Ala	synonymous	Exon 14 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.1299C>G	p.Ala433Ala	synonymous	Exon 14 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.1623C>G	p.Ala541Ala	synonymous	Exon 14 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1623C>G	p.Ala541Ala	synonymous	Exon 15 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.1299C>G	p.Ala433Ala	synonymous	Exon 14 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 23910 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: 0.00220 AC: 381 AN: 173232 AF XY: 0.00147

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000853

Gnomad OTH exome AF: 0.00149

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 23910 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11552

African (AFR) AF: 0.00 AC: 0 AN: 12050

American (AMR) AF: 0.00 AC: 0 AN: 1520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 306

East Asian (EAS) AF: 0.00 AC: 0 AN: 418

South Asian (SAS) AF: 0.00 AC: 0 AN: 538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1342

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 7394

Other (OTH) AF: 0.00 AC: 0 AN: 260

Alfa AF: 0.0000358 Hom.: 141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRODH: PM2:Supporting, BP4, BP7

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Proline dehydrogenase deficiency Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 Benign:1

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

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	-0.62
CADD	Benign	0.47
DANN	Benign	0.71
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs16983347; hg19: chr22-18900868;