22-18913156-A-G

Variant names:

• chr22-18913156-A-G
• rs383964
• ENST00000482858.5:n.4302T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000482858.5(PRODH):​n.4302T>C variant causes a non coding transcript exon 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 0.0028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.013 (1104 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH ENST00000482858.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.50
• Publications: 20 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-18913156-A-G is Benign according to our data. Variant chr22-18913156-A-G is described in ClinVar as Benign. ClinVar VariationId is 1298044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 1104 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000482858.5. 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.*19T>C		3_prime_UTR	Exon 14 of 14	NP_057419.5
	PRODH	NM_001195226.2		c.*19T>C		3_prime_UTR	Exon 14 of 14	NP_001182155.2
	PRODH	NM_001368250.2		c.*19T>C		3_prime_UTR	Exon 14 of 14	NP_001355179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRODH	ENST00000482858.5	TSL:1	n.4302T>C		non_coding_transcript_exon	Exon 11 of 11
	PRODH	ENST00000491604.5	TSL:1	n.2731T>C		non_coding_transcript_exon	Exon 13 of 13
	PRODH	ENST00000357068.11	TSL:1 MANE Select	c.*19T>C		3_prime_UTR	Exon 14 of 14	ENSP00000349577.6

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 63 AN: 22098 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00202

Gnomad ASJ AF: 0.00709

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00160

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.933 AC: 143559 AN: 153906 AF XY: 0.932

Gnomad AFR exome AF: 0.829

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.953

Gnomad EAS exome AF: 0.960

Gnomad FIN exome AF: 0.920

Gnomad NFE exome AF: 0.937

Gnomad OTH exome AF: 0.937

GnomAD4 exome AF: 0.0131 AC: 2262 AN: 172264 Hom.: 1104 Cov.: 0 AF XY: 0.0144 AC XY: 1228 AN XY: 85230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0603 AC: 569 AN: 9434

American (AMR) AF: 0.108 AC: 289 AN: 2678

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 12 AN: 2024

East Asian (EAS) AF: 0.0671 AC: 186 AN: 2770

South Asian (SAS) AF: 0.0367 AC: 479 AN: 13052

European-Finnish (FIN) AF: 0.0155 AC: 105 AN: 6788

Middle Eastern (MID) AF: 0.0102 AC: 8 AN: 784

European-Non Finnish (NFE) AF: 0.00372 AC: 473 AN: 127220

Other (OTH) AF: 0.0188 AC: 141 AN: 7514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00284 AC: 63 AN: 22162 Hom.: 0 Cov.: 0 AF XY: 0.00243 AC XY: 26 AN XY: 10698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00474 AC: 48 AN: 10132

American (AMR) AF: 0.00202 AC: 3 AN: 1486

Ashkenazi Jewish (ASJ) AF: 0.00709 AC: 2 AN: 282

East Asian (EAS) AF: 0.00270 AC: 1 AN: 370

South Asian (SAS) AF: 0.00160 AC: 1 AN: 626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.00105 AC: 8 AN: 7610

Other (OTH) AF: 0.00 AC: 0 AN: 264

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.770 Hom.: 11817

Asia WGS AF: 0.917 AC: 3190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Proline dehydrogenase deficiency Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.070
DANN	Benign	0.41
PhyloP100		-3.5
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: rs383964; hg19: chr22-18900669;