NM_016335.6:c.1644C>T

Variant names:

• chr22-18913334-G-A
• rs540773005
• NM_016335.6:c.1644C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_016335.6(PRODH):​c.1644C>T​(p.Tyr548Tyr) 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: 𝑓 0.000072 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0000083 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.536
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-18913334-G-A is Benign according to our data. Variant chr22-18913334-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2892154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.536 with no splicing effect.

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.1644C>T	p.Tyr548Tyr	synonymous	Exon 14 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.1320C>T	p.Tyr440Tyr	synonymous	Exon 14 of 14	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1320C>T	p.Tyr440Tyr	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.1644C>T	p.Tyr548Tyr	synonymous	Exon 14 of 14	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1644C>T	p.Tyr548Tyr	synonymous	Exon 15 of 15	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1320C>T	p.Tyr440Tyr	synonymous	Exon 14 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.0000719 AC: 2 AN: 27830 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000227 AC: 4 AN: 175862 AF XY: 0.0000106

Gnomad AFR exome AF: 0.0000965

Gnomad AMR exome AF: 0.0000744

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000826 AC: 3 AN: 363166 Hom.: 1 Cov.: 0 AF XY: 0.00000549 AC XY: 1 AN XY: 182186

African (AFR) AF: 0.000178 AC: 3 AN: 16824

American (AMR) AF: 0.00 AC: 0 AN: 13440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7408

East Asian (EAS) AF: 0.00 AC: 0 AN: 10604

South Asian (SAS) AF: 0.00 AC: 0 AN: 24722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2068

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 254728

Other (OTH) AF: 0.00 AC: 0 AN: 16934

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000719 AC: 2 AN: 27830 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 13512

African (AFR) AF: 0.000146 AC: 2 AN: 13658

American (AMR) AF: 0.00 AC: 0 AN: 1846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 378

East Asian (EAS) AF: 0.00 AC: 0 AN: 500

South Asian (SAS) AF: 0.00 AC: 0 AN: 628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 76

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8874

Other (OTH) AF: 0.00 AC: 0 AN: 322

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	-0.55
CADD	Benign	0.29
DANN	Benign	0.85
PhyloP100		-0.54

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: rs540773005; hg19: chr22-18900847; COSMIC: COSV58231399; COSMIC: COSV58231399;