rs148375080

Variant names:

• chr22-18925068-C-T
• rs148375080
• NM_016335.6:c.650G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_016335.6(PRODH):​c.650G>A​(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.092 (11 hom., cov: 0)
  • Exomes 𝑓: 0.11 (1681 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0210
• Publications: 9 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

ENSG00000283809 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011050582).
• BP6: Variant 22-18925068-C-T is Benign according to our data. Variant chr22-18925068-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547846.

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.650G>A	p.Arg217His	missense	Exon 4 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.326G>A	p.Arg109His	missense	Exon 4 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.326G>A	p.Arg109His	missense	Exon 4 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.650G>A	p.Arg217His	missense	Exon 4 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.650G>A	p.Arg217His	missense	Exon 5 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.326G>A	p.Arg109His	missense	Exon 4 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 26 AN: 282 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMR AF: 0.0714

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00472 AC: 1185 AN: 251136 AF XY: 0.00462

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00392

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.112 AC: 3477 AN: 31000 Hom.: 1681 Cov.: 0 AF XY: 0.105 AC XY: 1793 AN XY: 16996

African (AFR) AF: 0.0359 AC: 12 AN: 334

American (AMR) AF: 0.0203 AC: 34 AN: 1676

Ashkenazi Jewish (ASJ) AF: 0.0417 AC: 18 AN: 432

East Asian (EAS) AF: 0.00 AC: 0 AN: 1370

South Asian (SAS) AF: 0.0438 AC: 247 AN: 5636

European-Finnish (FIN) AF: 0.156 AC: 446 AN: 2850

Middle Eastern (MID) AF: 0.125 AC: 17 AN: 136

European-Non Finnish (NFE) AF: 0.150 AC: 2539 AN: 16892

Other (OTH) AF: 0.0980 AC: 164 AN: 1674

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0922 AC: 26 AN: 282 Hom.: 11 Cov.: 0 AF XY: 0.0846 AC XY: 11 AN XY: 130

African (AFR) AF: 0.00 AC: 0 AN: 22

American (AMR) AF: 0.0714 AC: 2 AN: 28

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 12

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.150 AC: 9 AN: 60

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.104 AC: 15 AN: 144

Other (OTH) AF: 0.00 AC: 0 AN: 4

Alfa AF: 0.00598 Hom.: 47

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00445 AC: 540

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Proline dehydrogenase deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.077	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.021
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.0060	B
Vest4		0.052
MVP		0.14
MPC		0.34
ClinPred		0.010	T
GERP RS		-2.2
gMVP		0.29
Mutation Taster		=98/2	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: rs148375080; hg19: chr22-18912581; COSMIC: COSV105189098; COSMIC: COSV105189098;