rs2238730

chr22-18918381-C-T

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.1362G>A(p.Ala454=) 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (18 hom., cov: 4)
  • Exomes 𝑓: 0.014 (215 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.07

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-18918381-C-T is Benign according to our data. Variant chr22-18918381-C-T is described in ClinVar as [Benign]. Clinvar id is 459910.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-7.07 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.1362G>A	p.Ala454=	synonymous_variant	11/14	ENST00000357068.11
PRODH	NM_001195226.2	c.1038G>A	p.Ala346=	synonymous_variant	11/14
PRODH	NM_001368250.2	c.1038G>A	p.Ala346=	synonymous_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.1362G>A	p.Ala454=	synonymous_variant	11/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 534 AN: 19278 Hom.: 17 Cov.: 4 FAILED QC

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.0870

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.00579

Gnomad EAS AF: 0.0103

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.00187

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.00778

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0142 AC: 3550 AN: 249354 Hom.: 66 AF XY: 0.0131 AC XY: 1773 AN XY: 134910

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.0133

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.00769

Gnomad NFE exome AF: 0.00975

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0144 AC: 3047 AN: 211424 Hom.: 215 Cov.: 0 AF XY: 0.0138 AC XY: 1543 AN XY: 111674

Gnomad4 AFR exome AF: 0.0693

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.00364

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0279 AC: 539 AN: 19328 Hom.: 18 Cov.: 4 AF XY: 0.0272 AC XY: 236 AN XY: 8662

Gnomad4 AFR AF: 0.0594

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.00579

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.00187

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.0216

Alfa AF: 0.0175 Hom.: 32

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 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	7.0
Dann	Benign	0.94

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: rs2238730; hg19: chr22-18905894; COSMIC: COSV58231049; COSMIC: COSV58231049;