22-18918465-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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 (★). Synonymous variant affecting the same amino acid position (i.e. D426D) has been classified as Likely benign.

• 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
• Publications: 16 publications found

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

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

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

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1278C>A	p.Asp426Glu	missense	Exon 11 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1278C>A	p.Asp426Glu	missense	Exon 12 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.954C>A	p.Asp318Glu	missense	Exon 11 of 14	ENSP00000334726.2

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

African (AFR) AF: 0.00 AC: 0 AN: 6980

American (AMR) AF: 0.00 AC: 0 AN: 7802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5024

East Asian (EAS) AF: 0.00 AC: 0 AN: 17318

South Asian (SAS) AF: 0.00 AC: 0 AN: 21908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 800

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 79304

Other (OTH) AF: 0.00 AC: 0 AN: 9126

GnomAD4 genome Cov.: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Proline dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.84	T
PhyloP100		-0.63
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.51
MutPred		0.58		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
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs16983466; hg19: chr22-18905978;