rs16983347

chr22-18913355-G-Achr22-18913355-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_016335.6(PRODH):c.1623C>T(p.Ala541=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 23,970 control chromosomes in the GnomAD database, including 2,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A541A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.23 (2524 hom., cov: 0)
  • Exomes 𝑓: 0.28 (39173 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.85

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]

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-18913355-G-A is Benign according to our data. Variant chr22-18913355-G-A is described in ClinVar as [Benign]. Clinvar id is 1166479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.1623C>T	p.Ala541=	synonymous_variant	14/14	ENST00000357068.11
PRODH	NM_001195226.2	c.1299C>T	p.Ala433=	synonymous_variant	14/14
PRODH	NM_001368250.2	c.1299C>T	p.Ala433=	synonymous_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.1623C>T	p.Ala541=	synonymous_variant	14/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes AF: 0.227 AC: 5419 AN: 23908 Hom.: 2525 Cov.: 0

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.0299 AC: 5176 AN: 173232 Hom.: 107 AF XY: 0.0311 AC XY: 2873 AN XY: 92430

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.000468

Gnomad SAS exome AF: 0.0405

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0298

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.278 AC: 86121 AN: 309388 Hom.: 39173 Cov.: 0 AF XY: 0.277 AC XY: 43203 AN XY: 155900

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.000938

Gnomad4 SAS exome AF: 0.243

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.339

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.226 AC: 5419 AN: 23970 Hom.: 2524 Cov.: 0 AF XY: 0.214 AC XY: 2481 AN XY: 11612

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.164

Alfa AF: 0.0338 Hom.: 115

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Proline dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.6
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16983347; hg19: chr22-18900868;