rs16983466

Variant names:

• chr22-18918465-G-A
• rs16983466
• NM_016335.6:c.1278C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-18918465-G-A
• chr22-18918465-G-T

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.1278C>T​(p.Asp426Asp) 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (83 hom., cov: 2)
  • Exomes 𝑓: 0.22 (6255 hom.)
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.632
• Publications: 16 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=-0.68).
• BP6: Variant 22-18918465-G-A is Benign according to our data. Variant chr22-18918465-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1166601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.632 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 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.1278C>T	p.Asp426Asp	synonymous	Exon 11 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.954C>T	p.Asp318Asp	synonymous	Exon 11 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.954C>T	p.Asp318Asp	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.1278C>T	p.Asp426Asp	synonymous	Exon 11 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1278C>T	p.Asp426Asp	synonymous	Exon 12 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.954C>T	p.Asp318Asp	synonymous	Exon 11 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 581 AN: 3082 Hom.: 83 Cov.: 2

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.0839

Gnomad SAS AF: 0.0991

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.144 AC: 35182 AN: 244830 AF XY: 0.141

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0620

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.218 AC: 33724 AN: 154810 Hom.: 6255 Cov.: 0 AF XY: 0.212 AC XY: 17516 AN XY: 82624

African (AFR) AF: 0.168 AC: 1168 AN: 6960

American (AMR) AF: 0.274 AC: 2132 AN: 7784

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 1238 AN: 5012

East Asian (EAS) AF: 0.104 AC: 1794 AN: 17298

South Asian (SAS) AF: 0.117 AC: 2550 AN: 21874

European-Finnish (FIN) AF: 0.336 AC: 2294 AN: 6828

Middle Eastern (MID) AF: 0.298 AC: 237 AN: 796

European-Non Finnish (NFE) AF: 0.256 AC: 20279 AN: 79148

Other (OTH) AF: 0.223 AC: 2032 AN: 9110

GnomAD4 genome AF: 0.189 AC: 583 AN: 3092 Hom.: 83 Cov.: 2 AF XY: 0.188 AC XY: 272 AN XY: 1446

African (AFR) AF: 0.160 AC: 147 AN: 918

American (AMR) AF: 0.194 AC: 70 AN: 360

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 12 AN: 62

East Asian (EAS) AF: 0.0854 AC: 27 AN: 316

South Asian (SAS) AF: 0.103 AC: 24 AN: 234

European-Finnish (FIN) AF: 0.242 AC: 30 AN: 124

Middle Eastern (MID) AF: 0.389 AC: 14 AN: 36

European-Non Finnish (NFE) AF: 0.252 AC: 242 AN: 962

Other (OTH) AF: 0.216 AC: 16 AN: 74

Alfa AF: 0.141 Hom.: 728

Asia WGS AF: 0.110 AC: 384 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Proline dehydrogenase deficiency (1)
-	-	1	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.19
DANN	Benign	0.89
PhyloP100		-0.63
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: rs16983466; hg19: chr22-18905978; COSMIC: COSV58229841; COSMIC: COSV58229841;