rs16983347

Variant names:

• chr22-18913355-G-A
• rs16983347
• NM_016335.6:c.1623C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-18913355-G-A
• chr22-18913355-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016335.6(PRODH):​c.1623C>T​(p.Ala541Ala) 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A541A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.23 (2524 hom., cov: 0)
  • Exomes 𝑓: 0.28 (39173 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.85
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-18913355-G-A is Benign according to our data. Variant chr22-18913355-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6	c.1623C>T	p.Ala541Ala	synonymous_variant	Exon 14 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2	c.1299C>T	p.Ala433Ala	synonymous_variant	Exon 14 of 14		NP_001182155.2
PRODH	NM_001368250.2	c.1299C>T	p.Ala433Ala	synonymous_variant	Exon 14 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11	c.1623C>T	p.Ala541Ala	synonymous_variant	Exon 14 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1	c.513+2327G>A		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 5419 AN: 23908 Hom.: 2525 Cov.: 0

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.0299 AC: 5176 AN: 173232 AF XY: 0.0311

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.000468

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0298

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.278 AC: 86121 AN: 309388 Hom.: 39173 Cov.: 0 AF XY: 0.277 AC XY: 43203 AN XY: 155900

African (AFR) AF: 0.0158 AC: 251 AN: 15906

American (AMR) AF: 0.0669 AC: 826 AN: 12350

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 1275 AN: 6098

East Asian (EAS) AF: 0.000938 AC: 8 AN: 8526

South Asian (SAS) AF: 0.243 AC: 5763 AN: 23684

European-Finnish (FIN) AF: 0.177 AC: 2425 AN: 13728

Middle Eastern (MID) AF: 0.177 AC: 319 AN: 1798

European-Non Finnish (NFE) AF: 0.339 AC: 72205 AN: 212946

Other (OTH) AF: 0.212 AC: 3049 AN: 14352

GnomAD4 genome AF: 0.226 AC: 5419 AN: 23970 Hom.: 2524 Cov.: 0 AF XY: 0.214 AC XY: 2481 AN XY: 11612

African (AFR) AF: 0.0295 AC: 357 AN: 12112

American (AMR) AF: 0.268 AC: 408 AN: 1520

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 166 AN: 306

East Asian (EAS) AF: 0.00 AC: 0 AN: 420

South Asian (SAS) AF: 0.292 AC: 156 AN: 534

European-Finnish (FIN) AF: 0.223 AC: 299 AN: 1342

Middle Eastern (MID) AF: 0.109 AC: 7 AN: 64

European-Non Finnish (NFE) AF: 0.539 AC: 3982 AN: 7392

Other (OTH) AF: 0.164 AC: 44 AN: 268

Alfa AF: 0.0323 Hom.: 141

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Proline dehydrogenase deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.6
DANN	Benign	0.85
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs16983347; hg19: chr22-18900868;