NM_016335.6:c.1735C>T

Variant names:

• chr22-18913243-G-A
• rs377373292
• NM_016335.6:c.1735C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_016335.6(PRODH):​c.1735C>T​(p.Arg579Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000026 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• Publications: 0 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]

ENSG00000283809 (HGNC:):

DGCR6 (HGNC:2846): (DiGeorge syndrome critical region gene 6) DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia. [provided by RefSeq, Nov 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000258 (13/503946) while in subpopulation MID AF = 0.00462 (12/2600). AF 95% confidence interval is 0.00266. There are 4 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 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.1735C>T	p.Arg579Trp	missense	Exon 14 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1411C>T	p.Arg471Trp	missense	Exon 14 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1411C>T	p.Arg471Trp	missense	Exon 14 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.1735C>T	p.Arg579Trp	missense	Exon 14 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1735C>T	p.Arg579Trp	missense	Exon 15 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1411C>T	p.Arg471Trp	missense	Exon 14 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 31614 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000495 AC: 8 AN: 161572 AF XY: 0.0000351

Gnomad AFR exome AF: 0.000109

Gnomad AMR exome AF: 0.0000396

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000258 AC: 13 AN: 503946 Hom.: 4 Cov.: 0 AF XY: 0.0000282 AC XY: 7 AN XY: 248194

African (AFR) AF: 0.00 AC: 0 AN: 19460

American (AMR) AF: 0.00 AC: 0 AN: 14450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8938

East Asian (EAS) AF: 0.00 AC: 0 AN: 11928

South Asian (SAS) AF: 0.00 AC: 0 AN: 26900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19254

Middle Eastern (MID) AF: 0.00462 AC: 12 AN: 2600

European-Non Finnish (NFE) AF: 0.00000264 AC: 1 AN: 378336

Other (OTH) AF: 0.00 AC: 0 AN: 22080

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 31614 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 15276

African (AFR) AF: 0.00 AC: 0 AN: 14846

American (AMR) AF: 0.00 AC: 0 AN: 2172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 464

East Asian (EAS) AF: 0.00 AC: 0 AN: 624

South Asian (SAS) AF: 0.00 AC: 0 AN: 746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 10494

Other (OTH) AF: 0.00 AC: 0 AN: 356

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000178 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.52	T
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.41
MPC		0.47
ClinPred		0.92	D
GERP RS		0.77
gMVP		0.85
Mutation Taster		=29/71	disease causing

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: rs377373292; hg19: chr22-18900756; COSMIC: COSV99044978; COSMIC: COSV99044978;