Genetic Variant NM_016335.6:c.1163C>A (chr22-18919539-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_016335.6(PRODH):c.1163C>A(p.Pro388Gln) 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.24

Publications

2 publications found

Variant links:

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)

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRODH	NM_016335.6	MANE Select	c.1163C>A	p.Pro388Gln	missense	Exon 10 of 14	NP_057419.5
PRODH	NM_001195226.2		c.839C>A	p.Pro280Gln	missense	Exon 10 of 14	NP_001182155.2
PRODH	NM_001368250.2		c.839C>A	p.Pro280Gln	missense	Exon 10 of 14	NP_001355179.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1163C>A	p.Pro388Gln	missense	Exon 10 of 14	ENSP00000349577.6
PRODH	ENST00000610940.4	TSL:1	c.1163C>A	p.Pro388Gln	missense	Exon 11 of 15	ENSP00000480347.1
PRODH	ENST00000334029.6	TSL:1	c.839C>A	p.Pro280Gln	missense	Exon 10 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249402

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.46

PhyloP100

9.2

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.79

MutPred

0.73

Gain of MoRF binding (P = 0.0667)

MVP

0.15

MPC

0.92

ClinPred

0.99

GERP RS

4.4

gMVP

0.72

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over