22-18918421-A-T

Position:

• chr22-18918421-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PP3_Strong

The NM_016335.6(PRODH):​c.1322T>A​(p.Leu441Gln) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L441P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 3)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.87

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-18918421-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4008.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=6, Likely_pathogenic=3}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.1322T>A	p.Leu441Gln	missense_variant	11/14	ENST00000357068.11
PRODH	NM_001195226.2	c.998T>A	p.Leu333Gln	missense_variant	11/14
PRODH	NM_001368250.2	c.998T>A	p.Leu333Gln	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.1322T>A	p.Leu441Gln	missense_variant	11/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 16, 2020

L441Q has not been previously published as pathogenic or benign to our knowledge; however, the L441P variant has been reported in the homozygous state in an individual with hyperprolinemia type I, and L441P leads to reduced stability of proline oxidase and significant reduction in its activity ((Jacquet et al., 2002; Bender et al., 2005; Cappelletti et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, supports that this missense variant has a deleterious effect on protein structure/function, but is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.97
MutPred		0.88		Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);
MVP		0.76
MPC		0.98
ClinPred		1.0	D
GERP RS		4.5
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-18905934;