22-18918465-G-T

Variant names:

• chr22-18918465-G-T
• rs16983466
• NM_016335.6:c.1278C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_016335.6(PRODH):​c.1278C>A​(p.Asp426Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. D426N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.632

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]

ENSG00000283809 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1278C>A	p.Asp426Glu	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.954C>A	p.Asp318Glu	missense_variant	Exon 11 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.954C>A	p.Asp318Glu	missense_variant	Exon 11 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1278C>A	p.Asp426Glu	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+7437G>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 155096 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Proline dehydrogenase deficiency Uncertain:1

Jan 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 426 of the PRODH protein (p.Asp426Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRODH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1903601). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRODH protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.92	D;.;D;.
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.84	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.7	.;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.51
MutPred		0.58		Loss of catalytic residue at D426 (P = 0.2595);.;.;Loss of catalytic residue at D426 (P = 0.2595);
MVP		0.014
MPC		0.91
ClinPred		0.99	D
GERP RS		-7.4
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs16983466; hg19: chr22-18905978;