chr22-18921347-C-T

Variant names:

• chr22-18921347-C-T
• rs1160517835
• NM_016335.6:c.1006G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016335.6(PRODH):​c.1006G>A​(p.Ala336Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.234
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03703481).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.1006G>A	p.Ala336Thr	missense	Exon 8 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.682G>A	p.Ala228Thr	missense	Exon 8 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.682G>A	p.Ala228Thr	missense	Exon 8 of 14	NP_001355179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1006G>A	p.Ala336Thr	missense	Exon 8 of 14	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1006G>A	p.Ala336Thr	missense	Exon 9 of 15	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.682G>A	p.Ala228Thr	missense	Exon 8 of 14	ENSP00000334726.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 160816 AF XY: 0.0000236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000530 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Proline dehydrogenase deficiency (1)
-	1	-	Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.0
DANN	Benign	0.87
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.23
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.067
Sift	Benign	0.62	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.53		Gain of sheet (P = 0.0344)
MVP		0.030
MPC		0.27
ClinPred		0.026	T
GERP RS		-5.1
gMVP		0.32
Mutation Taster		=97/3	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: rs1160517835; hg19: chr22-18908860; COSMIC: COSV58230198; COSMIC: COSV58230198;