chr22-18918451-C-T

Variant names:

• chr22-18918451-C-T
• rs2904552
• NM_016335.6:c.1292G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016335.6(PRODH):​c.1292G>A​(p.Arg431His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.051 (15 hom., cov: 2)
  • Exomes 𝑓: 0.10 (2136 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:4 O:1
• Conservation: PhyloP100: 1.45
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036971867).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.1292G>A	p.Arg431His	missense	Exon 11 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.968G>A	p.Arg323His	missense	Exon 11 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.968G>A	p.Arg323His	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.1292G>A	p.Arg431His	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1292G>A	p.Arg431His	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.968G>A	p.Arg323His	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 283 AN: 5570 Hom.: 15 Cov.: 2

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0370

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.0660

GnomAD2 exomes AF: 0.0723 AC: 17881 AN: 247476 AF XY: 0.0738

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.000656

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0829

GnomAD4 exome AF: 0.103 AC: 17301 AN: 168500 Hom.: 2136 Cov.: 0 AF XY: 0.0995 AC XY: 8911 AN XY: 89530

African (AFR) AF: 0.0328 AC: 249 AN: 7580

American (AMR) AF: 0.0685 AC: 563 AN: 8220

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 764 AN: 5534

East Asian (EAS) AF: 0.000642 AC: 13 AN: 20260

South Asian (SAS) AF: 0.0519 AC: 1079 AN: 20808

European-Finnish (FIN) AF: 0.0682 AC: 552 AN: 8094

Middle Eastern (MID) AF: 0.102 AC: 91 AN: 894

European-Non Finnish (NFE) AF: 0.148 AC: 12857 AN: 86894

Other (OTH) AF: 0.111 AC: 1133 AN: 10216

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0509 AC: 284 AN: 5584 Hom.: 15 Cov.: 2 AF XY: 0.0496 AC XY: 123 AN XY: 2482

African (AFR) AF: 0.0216 AC: 38 AN: 1756

American (AMR) AF: 0.0466 AC: 30 AN: 644

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 9 AN: 114

East Asian (EAS) AF: 0.00 AC: 0 AN: 462

South Asian (SAS) AF: 0.0271 AC: 9 AN: 332

European-Finnish (FIN) AF: 0.0414 AC: 11 AN: 266

Middle Eastern (MID) AF: 0.0370 AC: 2 AN: 54

European-Non Finnish (NFE) AF: 0.0957 AC: 176 AN: 1840

Other (OTH) AF: 0.0625 AC: 7 AN: 112

Alfa AF: 0.0926 Hom.: 1111

TwinsUK AF: 0.102 AC: 379

ALSPAC AF: 0.112 AC: 431

ESP6500AA AF: 0.0366 AC: 161

ESP6500EA AF: 0.105 AC: 900

ExAC AF: 0.0746 AC: 9050

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.2	T
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.032	D
Polyphen		0.94	P
Vest4		0.16
MPC		0.44
ClinPred		0.033	T
GERP RS		1.2
gMVP		0.62
Mutation Taster		=97/3	disease causing (ClinVar)

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: rs2904552; hg19: chr22-18905964; COSMIC: COSV58230523; COSMIC: COSV58230523;