NM_016335.6:c.1357C>T

Variant names:

• chr22-18918386-G-A
• rs3970559
• NM_016335.6:c.1357C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016335.6(PRODH):​c.1357C>T​(p.Arg453Cys) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (12 hom., cov: 4)
  • Exomes 𝑓: 0.013 (181 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3 O:1
• Conservation: PhyloP100: 2.03
• Publications: 19 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012216002).
• BP6: Variant 22-18918386-G-A is Benign according to our data. Variant chr22-18918386-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4006.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0125 (2640/211074) while in subpopulation AFR AF = 0.0384 (329/8564). AF 95% confidence interval is 0.035. There are 181 homozygotes in GnomAdExome4. There are 1348 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 181 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.1357C>T	p.Arg453Cys	missense	Exon 11 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1033C>T	p.Arg345Cys	missense	Exon 11 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1033C>T	p.Arg345Cys	missense	Exon 11 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1357C>T	p.Arg453Cys	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1357C>T	p.Arg453Cys	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1033C>T	p.Arg345Cys	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 332 AN: 18570 Hom.: 12 Cov.: 4

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.00602

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.00289

Gnomad MID AF: 0.0111

Gnomad NFE AF: 0.00754

Gnomad OTH AF: 0.0155

GnomAD2 exomes AF: 0.0108 AC: 2704 AN: 249400 AF XY: 0.0106

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.00737

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00802

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0125 AC: 2640 AN: 211074 Hom.: 181 Cov.: 0 AF XY: 0.0121 AC XY: 1348 AN XY: 111248

African (AFR) AF: 0.0384 AC: 329 AN: 8564

American (AMR) AF: 0.0173 AC: 167 AN: 9642

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 108 AN: 7036

East Asian (EAS) AF: 0.0135 AC: 342 AN: 25290

South Asian (SAS) AF: 0.00902 AC: 200 AN: 22176

European-Finnish (FIN) AF: 0.00240 AC: 29 AN: 12082

Middle Eastern (MID) AF: 0.0128 AC: 14 AN: 1098

European-Non Finnish (NFE) AF: 0.0112 AC: 1258 AN: 112378

Other (OTH) AF: 0.0151 AC: 193 AN: 12808

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0180 AC: 335 AN: 18618 Hom.: 12 Cov.: 4 AF XY: 0.0183 AC XY: 152 AN XY: 8320

African (AFR) AF: 0.0314 AC: 193 AN: 6156

American (AMR) AF: 0.0266 AC: 51 AN: 1916

Ashkenazi Jewish (ASJ) AF: 0.00602 AC: 3 AN: 498

East Asian (EAS) AF: 0.0161 AC: 15 AN: 930

South Asian (SAS) AF: 0.0112 AC: 7 AN: 624

European-Finnish (FIN) AF: 0.00289 AC: 3 AN: 1038

Middle Eastern (MID) AF: 0.0122 AC: 1 AN: 82

European-Non Finnish (NFE) AF: 0.00755 AC: 53 AN: 7024

Other (OTH) AF: 0.0146 AC: 4 AN: 274

Alfa AF: 0.0124 Hom.: 16

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.0125 AC: 1516

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
1	-	1	Proline dehydrogenase deficiency (2)
-	1	-	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)
-	-	-	Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.53	T
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.32
MPC		1.1
ClinPred		0.14	T
GERP RS		3.2
gMVP		0.82
Mutation Taster		=91/9	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: rs3970559; hg19: chr22-18905899; COSMIC: COSV58230280; COSMIC: COSV58230280;