22-18913156-A-G

Position:

• chr22-18913156-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016335.6(PRODH):​c.*19T>C variant causes a 3 prime UTR 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 0.0028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.013 (1104 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.50

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-18913156-A-G is Benign according to our data. Variant chr22-18913156-A-G is described in ClinVar as [Benign]. Clinvar id is 1298044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18913156-A-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.*19T>C		3_prime_UTR_variant	14/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.*19T>C		3_prime_UTR_variant	14/14		NP_001182155.2
PRODH	NM_001368250.2	c.*19T>C		3_prime_UTR_variant	14/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068	c.*19T>C		3_prime_UTR_variant	14/14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+2128A>G		intron_variant		5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 63 AN: 22098 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00202

Gnomad ASJ AF: 0.00709

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00160

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.933 AC: 143559 AN: 153906 Hom.: 67052 AF XY: 0.932 AC XY: 76258 AN XY: 81798

Gnomad AFR exome AF: 0.829

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.953

Gnomad EAS exome AF: 0.960

Gnomad SAS exome AF: 0.911

Gnomad FIN exome AF: 0.920

Gnomad NFE exome AF: 0.937

Gnomad OTH exome AF: 0.937

GnomAD4 exome AF: 0.0131 AC: 2262 AN: 172264 Hom.: 1104 Cov.: 0 AF XY: 0.0144 AC XY: 1228 AN XY: 85230

Gnomad4 AFR exome AF: 0.0603

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.00593

Gnomad4 EAS exome AF: 0.0671

Gnomad4 SAS exome AF: 0.0367

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00284 AC: 63 AN: 22162 Hom.: 0 Cov.: 0 AF XY: 0.00243 AC XY: 26 AN XY: 10698

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.00709

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00160

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00

Alfa AF: 0.770 Hom.: 11817

Asia WGS AF: 0.917 AC: 3190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2018	- -

Proline dehydrogenase deficiency Benign:1

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	-0.97
CADD	Benign	0.070
DANN	Benign	0.41

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: rs383964; hg19: chr22-18900669;