NM_016335.6:c.1163C>G

Variant names:

• chr22-18919539-G-C
• rs147233639
• NM_016335.6:c.1163C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_016335.6(PRODH):​c.1163C>G​(p.Pro388Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P388L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 0)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

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.1163C>G	p.Pro388Arg	missense	Exon 10 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.839C>G	p.Pro280Arg	missense	Exon 10 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.839C>G	p.Pro280Arg	missense	Exon 10 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.1163C>G	p.Pro388Arg	missense	Exon 10 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1163C>G	p.Pro388Arg	missense	Exon 11 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.839C>G	p.Pro280Arg	missense	Exon 10 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.38	T
PhyloP100		9.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.72		Gain of MoRF binding (P = 0.0013)
MVP		0.20
MPC		0.99
ClinPred		1.0	D
GERP RS		4.4
gMVP		0.81
Mutation Taster		=17/83	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: rs147233639; hg19: chr22-18907052;