rs372055

chr22-18913237-G-Achr22-18913237-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_016335.6(PRODH):c.1741C>T(p.Leu581=) variant causes a synonymous change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000032 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000016 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.17

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 22-18913237-G-A is Benign according to our data. Variant chr22-18913237-G-A is described in ClinVar as [Benign]. Clinvar id is 127267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18913237-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 49346 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.1741C>T	p.Leu581=	synonymous_variant	14/14	ENST00000357068.11
PRODH	NM_001195226.2	c.1417C>T	p.Leu473=	synonymous_variant	14/14
PRODH	NM_001368250.2	c.1417C>T	p.Leu473=	synonymous_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.1741C>T	p.Leu581=	synonymous_variant	14/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 31630 Hom.: 0 Cov.: 0 FAILED QC

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

GnomAD3 exomes AF: 0.783 AC: 125626 AN: 160360 Hom.: 49346 AF XY: 0.789 AC XY: 66993 AN XY: 84882

Gnomad AFR exome AF: 0.620

Gnomad AMR exome AF: 0.762

Gnomad ASJ exome AF: 0.804

Gnomad EAS exome AF: 0.840

Gnomad SAS exome AF: 0.812

Gnomad FIN exome AF: 0.756

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.775

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000158 AC: 8 AN: 505186 Hom.: 3 Cov.: 0 AF XY: 0.0000281 AC XY: 7 AN XY: 248788

Gnomad4 AFR exome AF: 0.0000514

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000315 AC: 1 AN: 31716 Hom.: 0 Cov.: 0 AF XY: 0.0000650 AC XY: 1 AN XY: 15382

Gnomad4 AFR AF: 0.0000671

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.637 Hom.: 15879

Asia WGS AF: 0.762 AC: 2649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2018	- -

Proline dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	7.3
Dann	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs372055; hg19: chr22-18900750; COSMIC: COSV58230985; COSMIC: COSV58230985;