chr22-18918346-G-T

Position:

• chr22-18918346-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_016335.6(PRODH):​c.1397C>A​(p.Thr466Lys) variant causes a missense change. 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. T466M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 5)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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 Uncertain_significance. Variant got 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1397C>A	p.Thr466Lys	missense_variant	11/14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1073C>A	p.Thr358Lys	missense_variant	11/14		NP_001182155.2
PRODH	NM_001368250.2	c.1073C>A	p.Thr358Lys	missense_variant	11/14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1397C>A	p.Thr466Lys	missense_variant	11/14	1	NM_016335.6	ENSP00000349577	P3

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Proline dehydrogenase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;.;D;.
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	.;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.031	.;D;D;D
Sift4G	Benign	0.067	T;T;T;T
Polyphen		0.86	.;P;P;.
Vest4		0.53
MutPred		0.64		Gain of ubiquitination at T466 (P = 0.0114);.;.;Gain of ubiquitination at T466 (P = 0.0114);
MVP		0.040
MPC		0.67
ClinPred		0.97	D
GERP RS		3.1
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2870984; hg19: chr22-18905859;