NM_016335.6:c.1674G>A

Variant names:

• chr22-18913304-C-T
• rs758860516
• NM_016335.6:c.1674G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_016335.6(PRODH):​c.1674G>A​(p.Leu558Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000013 (2 hom.)
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.625
• Publications: 1 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]

ENSG00000283809 (HGNC:):

DGCR6 (HGNC:2846): (DiGeorge syndrome critical region gene 6) DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia. [provided by RefSeq, Nov 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 22-18913304-C-T is Benign according to our data. Variant chr22-18913304-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1931036.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.625 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.1674G>A	p.Leu558Leu	synonymous	Exon 14 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1350G>A	p.Leu450Leu	synonymous	Exon 14 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1350G>A	p.Leu450Leu	synonymous	Exon 14 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.1674G>A	p.Leu558Leu	synonymous	Exon 14 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1674G>A	p.Leu558Leu	synonymous	Exon 15 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1350G>A	p.Leu450Leu	synonymous	Exon 14 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000126 AC: 5 AN: 397412 Hom.: 2 Cov.: 0 AF XY: 0.0000150 AC XY: 3 AN XY: 199460

African (AFR) AF: 0.000289 AC: 5 AN: 17302

American (AMR) AF: 0.00 AC: 0 AN: 13346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7888

East Asian (EAS) AF: 0.00 AC: 0 AN: 11522

South Asian (SAS) AF: 0.00 AC: 0 AN: 25048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 283548

Other (OTH) AF: 0.00 AC: 0 AN: 18426

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.7
DANN	Benign	0.95
PhyloP100		0.63

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: rs758860516; hg19: chr22-18900817;