rs2238730

Variant names:

• chr22-18918381-C-T
• rs2238730
• NM_016335.6:c.1362G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016335.6(PRODH):​c.1362G>A​(p.Ala454Ala) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -7.07
• Publications: 6 publications found

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]

PRODH Gene-Disease associations (from GenCC):

• hyperprolinemia type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 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 VariationId is 459910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.1362G>A	p.Ala454Ala	synonymous	Exon 11 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1038G>A	p.Ala346Ala	synonymous	Exon 11 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.1038G>A	p.Ala346Ala	synonymous	Exon 11 of 14	NP_001355179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1362G>A	p.Ala454Ala	synonymous	Exon 11 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1362G>A	p.Ala454Ala	synonymous	Exon 12 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.1038G>A	p.Ala346Ala	synonymous	Exon 11 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 534 AN: 19278 Hom.: 17 Cov.: 4

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

GnomAD2 exomes AF: 0.0142 AC: 3550 AN: 249354 AF XY: 0.0131

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 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

African (AFR) AF: 0.0693 AC: 594 AN: 8572

American (AMR) AF: 0.0198 AC: 193 AN: 9772

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 89 AN: 7008

East Asian (EAS) AF: 0.0135 AC: 341 AN: 25310

South Asian (SAS) AF: 0.0110 AC: 248 AN: 22474

European-Finnish (FIN) AF: 0.00364 AC: 44 AN: 12076

Middle Eastern (MID) AF: 0.0154 AC: 17 AN: 1102

European-Non Finnish (NFE) AF: 0.0114 AC: 1286 AN: 112350

Other (OTH) AF: 0.0184 AC: 235 AN: 12760

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

African (AFR) AF: 0.0594 AC: 380 AN: 6392

American (AMR) AF: 0.0325 AC: 64 AN: 1970

Ashkenazi Jewish (ASJ) AF: 0.00579 AC: 3 AN: 518

East Asian (EAS) AF: 0.0104 AC: 10 AN: 962

South Asian (SAS) AF: 0.0125 AC: 8 AN: 642

European-Finnish (FIN) AF: 0.00187 AC: 2 AN: 1072

Middle Eastern (MID) AF: 0.0119 AC: 1 AN: 84

European-Non Finnish (NFE) AF: 0.00779 AC: 57 AN: 7318

Other (OTH) AF: 0.0216 AC: 6 AN: 278

Alfa AF: 0.0175 Hom.: 32

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Proline dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.0
DANN	Benign	0.94
PhyloP100		-7.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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