rs1076466

chr22-18919611-G-Achr22-18919611-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016335.6(PRODH):c.1105-14C>T variant causes a splice polypyrimidine tract, intron 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 0.60 (56 hom., cov: 0)
  • Exomes 𝑓: 0.66 (3495 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.299

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 22-18919611-G-A is Benign according to our data. Variant chr22-18919611-G-A is described in ClinVar as [Benign]. Clinvar id is 1169512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18919611-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 25925 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.1105-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357068.11
PRODH	NM_001195226.2	c.781-14C>T		splice_polypyrimidine_tract_variant, intron_variant
PRODH	NM_001368250.2	c.781-14C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.1105-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_016335.6	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 150 AN: 250 Hom.: 56 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.517

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.750

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.667

GnomAD3 exomes AF: 0.457 AC: 109476 AN: 239750 Hom.: 25925 AF XY: 0.464 AC XY: 60226 AN XY: 129864

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.748

Gnomad SAS exome AF: 0.614

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.426

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.664 AC: 9927 AN: 14960 Hom.: 3495 Cov.: 0 AF XY: 0.669 AC XY: 5417 AN XY: 8094

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.593

Gnomad4 ASJ exome AF: 0.660

Gnomad4 EAS exome AF: 0.898

Gnomad4 SAS exome AF: 0.775

Gnomad4 FIN exome AF: 0.597

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.628

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.603 AC: 152 AN: 252 Hom.: 56 Cov.: 0 AF XY: 0.591 AC XY: 65 AN XY: 110

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.750

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.667

Alfa AF: 0.376 Hom.: 1398

Asia WGS AF: 0.633 AC: 2199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Proline dehydrogenase deficiency Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	2.1
Dann	Benign	0.85

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: rs1076466; hg19: chr22-18907124; COSMIC: COSV58229941; COSMIC: COSV58229941;