rs2238731

Variant names:

• chr22-18918464-C-T
• rs2238731
• NM_016335.6:c.1279G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016335.6(PRODH):​c.1279G>A​(p.Val427Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (4 hom., cov: 2)
  • Exomes 𝑓: 0.036 (394 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.286
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030622482).
• BP6: Variant 22-18918464-C-T is Benign according to our data. Variant chr22-18918464-C-T is described in ClinVar as Benign. ClinVar VariationId is 459909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0996 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.1279G>A	p.Val427Met	missense	Exon 11 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.955G>A	p.Val319Met	missense	Exon 11 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.955G>A	p.Val319Met	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.1279G>A	p.Val427Met	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1279G>A	p.Val427Met	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.955G>A	p.Val319Met	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 120 AN: 3904 Hom.: 4 Cov.: 2

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.00385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0109

GnomAD2 exomes AF: 0.0384 AC: 9422 AN: 245360 AF XY: 0.0330

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.00295

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0357 AC: 5726 AN: 160352 Hom.: 394 Cov.: 0 AF XY: 0.0331 AC XY: 2826 AN XY: 85352

African (AFR) AF: 0.0738 AC: 529 AN: 7168

American (AMR) AF: 0.0904 AC: 729 AN: 8064

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 73 AN: 5226

East Asian (EAS) AF: 0.104 AC: 1847 AN: 17838

South Asian (SAS) AF: 0.0109 AC: 240 AN: 21968

European-Finnish (FIN) AF: 0.00501 AC: 37 AN: 7384

Middle Eastern (MID) AF: 0.0175 AC: 15 AN: 856

European-Non Finnish (NFE) AF: 0.0230 AC: 1897 AN: 82340

Other (OTH) AF: 0.0378 AC: 359 AN: 9508

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0302 AC: 118 AN: 3912 Hom.: 4 Cov.: 2 AF XY: 0.0329 AC XY: 59 AN XY: 1796

African (AFR) AF: 0.0412 AC: 48 AN: 1166

American (AMR) AF: 0.0508 AC: 24 AN: 472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 78

East Asian (EAS) AF: 0.0872 AC: 30 AN: 344

South Asian (SAS) AF: 0.00382 AC: 1 AN: 262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 42

European-Non Finnish (NFE) AF: 0.0101 AC: 13 AN: 1284

Other (OTH) AF: 0.0208 AC: 2 AN: 96

Alfa AF: 0.0227 Hom.: 142

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.0795 AC: 350

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.0362 AC: 4393

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Proline dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.29
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.037
Sift	Benign	0.50	T
Sift4G	Benign	0.34	T
Polyphen		0.35	B
Vest4		0.074
MPC		0.30
ClinPred		0.0020	T
GERP RS		-1.1
gMVP		0.59
Mutation Taster		=98/2	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: rs2238731; hg19: chr22-18905977; COSMIC: COSV58230771; COSMIC: COSV58230771;