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GeneBe

rs2904550

chr22-18918369-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_016335.6(PRODH):c.1374C>A(p.Gly458=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 235,584 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.022 ( 24 hom., cov: 4)
Exomes 𝑓: 0.023 ( 539 hom. )

Consequence

PRODH
NM_016335.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.78
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 22-18918369-G-T is Benign according to our data. Variant chr22-18918369-G-T is described in ClinVar as [Benign]. Clinvar id is 459911.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=2.78 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0216 (492/22792) while in subpopulation SAS AF= 0.0529 (37/700). AF 95% confidence interval is 0.0394. There are 24 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRODHNM_016335.6 linkuse as main transcriptc.1374C>A p.Gly458= synonymous_variant 11/14 ENST00000357068.11
PRODHNM_001195226.2 linkuse as main transcriptc.1050C>A p.Gly350= synonymous_variant 11/14
PRODHNM_001368250.2 linkuse as main transcriptc.1050C>A p.Gly350= synonymous_variant 11/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRODHENST00000357068.11 linkuse as main transcriptc.1374C>A p.Gly458= synonymous_variant 11/141 NM_016335.6 P3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0217
AC:
493
AN:
22736
Hom.:
24
Cov.:
4
show subpopulations
Gnomad AFR
AF:
0.0151
Gnomad AMI
AF:
0.0263
Gnomad AMR
AF:
0.0220
Gnomad ASJ
AF:
0.00651
Gnomad EAS
AF:
0.0267
Gnomad SAS
AF:
0.0533
Gnomad FIN
AF:
0.0993
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0149
Gnomad OTH
AF:
0.0195
GnomAD3 exomes
AF:
0.0237
AC:
5916
AN:
249230
Hom.:
132
AF XY:
0.0241
AC XY:
3251
AN XY:
134802
show subpopulations
Gnomad AFR exome
AF:
0.0180
Gnomad AMR exome
AF:
0.0157
Gnomad ASJ exome
AF:
0.00609
Gnomad EAS exome
AF:
0.0218
Gnomad SAS exome
AF:
0.0387
Gnomad FIN exome
AF:
0.0528
Gnomad NFE exome
AF:
0.0190
Gnomad OTH exome
AF:
0.0294
GnomAD4 exome
AF:
0.0232
AC:
4947
AN:
212792
Hom.:
539
Cov.:
0
AF XY:
0.0238
AC XY:
2676
AN XY:
112306
show subpopulations
Gnomad4 AFR exome
AF:
0.0160
Gnomad4 AMR exome
AF:
0.0153
Gnomad4 ASJ exome
AF:
0.0115
Gnomad4 EAS exome
AF:
0.0218
Gnomad4 SAS exome
AF:
0.0373
Gnomad4 FIN exome
AF:
0.102
Gnomad4 NFE exome
AF:
0.0138
Gnomad4 OTH exome
AF:
0.0260
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0216
AC:
492
AN:
22792
Hom.:
24
Cov.:
4
AF XY:
0.0246
AC XY:
254
AN XY:
10322
show subpopulations
Gnomad4 AFR
AF:
0.0151
Gnomad4 AMR
AF:
0.0219
Gnomad4 ASJ
AF:
0.00651
Gnomad4 EAS
AF:
0.0259
Gnomad4 SAS
AF:
0.0529
Gnomad4 FIN
AF:
0.0993
Gnomad4 NFE
AF:
0.0149
Gnomad4 OTH
AF:
0.0155
Alfa
AF:
0.0186
Hom.:
30
Asia WGS
AF:
0.0400
AC:
138
AN:
3478
EpiCase
AF:
0.0235
EpiControl
AF:
0.0178

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
Cadd
Benign
5.0
Dann
Benign
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2904550; hg19: chr22-18905882; COSMIC: COSV100471760; COSMIC: COSV100471760; API