rs1076466

Variant names:

• chr22-18919611-G-A
• rs1076466
• NM_016335.6:c.1105-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-18919611-G-A
• chr22-18919611-G-C
• chr22-18919611-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_016335.6(PRODH):​c.1105-14C>T variant causes a intron 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (56 hom., cov: 0)
  • Exomes 𝑓: 0.66 (3495 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.299
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.006).
• BP6: Variant 22-18919611-G-A is Benign according to our data. Variant chr22-18919611-G-A is described in ClinVar as Benign. ClinVar VariationId is 1169512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	NM_016335.6	MANE Select	c.1105-14C>T		intron	N/A	NP_057419.5
	PRODH	NM_001195226.2		c.781-14C>T		intron	N/A	NP_001182155.2
	PRODH	NM_001368250.2		c.781-14C>T		intron	N/A	NP_001355179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1105-14C>T		intron	N/A	ENSP00000349577.6
	PRODH	ENST00000610940.4	TSL:1	c.1105-14C>T		intron	N/A	ENSP00000480347.1
	PRODH	ENST00000334029.6	TSL:1	c.781-14C>T		intron	N/A	ENSP00000334726.2

Frequencies

GnomAD3 genomes AF: 0.600 AC: 150 AN: 250 Hom.: 56 Cov.: 0

Gnomad AFR AF: 0.517

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.750

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.457 AC: 109476 AN: 239750 AF XY: 0.464

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.748

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.426

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.664 AC: 9927 AN: 14960 Hom.: 3495 Cov.: 0 AF XY: 0.669 AC XY: 5417 AN XY: 8094

African (AFR) AF: 0.592 AC: 529 AN: 894

American (AMR) AF: 0.593 AC: 553 AN: 932

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 380 AN: 576

East Asian (EAS) AF: 0.898 AC: 2194 AN: 2442

South Asian (SAS) AF: 0.775 AC: 1186 AN: 1530

European-Finnish (FIN) AF: 0.597 AC: 363 AN: 608

Middle Eastern (MID) AF: 0.574 AC: 54 AN: 94

European-Non Finnish (NFE) AF: 0.587 AC: 4056 AN: 6910

Other (OTH) AF: 0.628 AC: 612 AN: 974

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.603 AC: 152 AN: 252 Hom.: 56 Cov.: 0 AF XY: 0.591 AC XY: 65 AN XY: 110

African (AFR) AF: 0.533 AC: 32 AN: 60

American (AMR) AF: 0.521 AC: 25 AN: 48

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.852 AC: 46 AN: 54

South Asian (SAS) AF: 0.750 AC: 15 AN: 20

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.450 AC: 27 AN: 60

Other (OTH) AF: 0.667 AC: 4 AN: 6

Alfa AF: 0.376 Hom.: 1398

Asia WGS AF: 0.633 AC: 2199 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.1
DANN	Benign	0.85
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs1076466; hg19: chr22-18907124; COSMIC: COSV58229941; COSMIC: COSV58229941;