rs1555890224

Variant names:

• chr22-18918325-A-G
• rs1555890224
• NM_016335.6:c.1418T>C
• PRODH p.Met473Thr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_016335.6(PRODH):​c.1418T>C​(p.Met473Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 5)
  • 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: 5.63
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

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.1418T>C	p.Met473Thr	missense	Exon 11 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1094T>C	p.Met365Thr	missense	Exon 11 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1094T>C	p.Met365Thr	missense	Exon 11 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1418T>C	p.Met473Thr	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1418T>C	p.Met473Thr	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1094T>C	p.Met365Thr	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 136254 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71906

African (AFR) AF: 0.00 AC: 0 AN: 6130

American (AMR) AF: 0.00 AC: 0 AN: 6354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4492

East Asian (EAS) AF: 0.00 AC: 0 AN: 17966

South Asian (SAS) AF: 0.00 AC: 0 AN: 13338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 70976

Other (OTH) AF: 0.00 AC: 0 AN: 8250

GnomAD4 genome Cov.: 5

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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	Benign	0.14
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.035
Eigen_PC	Benign	0.028
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.0	T
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.29
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
gMVP		0.78
Mutation Taster		=11/89	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555890224;

hg19: chr22-18905838;