dbSNP rs5747933: PRODH:p.Thr275Asn (chr22-18922842-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_016335.6(PRODH):c.824C>A(p.Thr275Asn) 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: not found (cov: 0)

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.00

Publications

25 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017009974).

BP6

Variant 22-18922842-G-T is Benign according to our data. Variant chr22-18922842-G-T is described in ClinVar as Benign. ClinVar VariationId is 1168805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	UniProt
PRODH	NM_016335.6	MANE Select	c.824C>A	p.Thr275Asn	missense	Exon 6 of 14	NP_057419.5
PRODH	NM_001195226.2		c.500C>A	p.Thr167Asn	missense	Exon 6 of 14	NP_001182155.2	O43272-2
PRODH	NM_001368250.2		c.500C>A	p.Thr167Asn	missense	Exon 6 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	ENST00000357068.11	TSL:1 MANE Select	c.824C>A	p.Thr275Asn	missense	Exon 6 of 14	ENSP00000349577.6	O43272-4
PRODH	ENST00000610940.4	TSL:1	c.824C>A	p.Thr275Asn	missense	Exon 7 of 15	ENSP00000480347.1	O43272-4
PRODH	ENST00000334029.6	TSL:1	c.500C>A	p.Thr167Asn	missense	Exon 6 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0644

AC:

16175

AN:

251154

AF XY:

0.0596

show subpopulations

Gnomad AFR exome

AF:

0.00942

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.0725

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0436

Gnomad OTH exome

AF:

0.0613

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0470

Hom.:

337

TwinsUK

AF:

0.0437

AC:

162

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0427

AC:

367

ExAC

AF:

0.0577

AC:

7002

Asia WGS

AF:

0.0870

AC:

301

AN:

3478

EpiCase

AF:

0.0493

EpiControl

AF:

0.0480

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Proline dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.012

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

PhyloP100

0.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.27

REVEL

Benign

0.021

Sift

Benign

0.60

Sift4G

Benign

0.54

Polyphen

0.37

Vest4

0.19

MPC

0.33

ClinPred

0.0037

GERP RS

0.76

gMVP

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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