rs385440

Variant names:

• chr22-18913577-A-G
• rs385440
• NM_016335.6:c.1527-51T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-18913577-A-G
• chr22-18913577-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016335.6(PRODH):​c.1527-51T>C 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 0.000074 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000086 (6 hom.)
• Consequence: PRODH NM_016335.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.514
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-18913577-A-G is Benign according to our data. Variant chr22-18913577-A-G is described in ClinVar as Benign. ClinVar VariationId is 1223981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000862 (12/139182) while in subpopulation SAS AF = 0.000456 (6/13146). AF 95% confidence interval is 0.000199. There are 6 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1527-51T>C		intron	N/A	NP_057419.5
	PRODH	NM_001195226.2		c.1203-51T>C		intron	N/A	NP_001182155.2	O43272-2
	PRODH	NM_001368250.2		c.1203-51T>C		intron	N/A	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.1527-51T>C		intron	N/A	ENSP00000349577.6	O43272-4
	PRODH	ENST00000610940.4	TSL:1	c.1527-51T>C		intron	N/A	ENSP00000480347.1	O43272-4
	PRODH	ENST00000334029.6	TSL:1	c.1203-51T>C		intron	N/A	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes AF: 0.0000736 AC: 2 AN: 27172 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000143

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: 0.913 AC: 142541 AN: 156058 AF XY: 0.916

Gnomad AFR exome AF: 0.644

Gnomad AMR exome AF: 0.951

Gnomad ASJ exome AF: 0.948

Gnomad EAS exome AF: 0.907

Gnomad FIN exome AF: 0.920

Gnomad NFE exome AF: 0.935

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.0000862 AC: 12 AN: 139182 Hom.: 6 Cov.: 0 AF XY: 0.000140 AC XY: 10 AN XY: 71436

African (AFR) AF: 0.000165 AC: 2 AN: 12142

American (AMR) AF: 0.00 AC: 0 AN: 3454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2144

East Asian (EAS) AF: 0.00 AC: 0 AN: 4614

South Asian (SAS) AF: 0.000456 AC: 6 AN: 13146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 972

European-Non Finnish (NFE) AF: 0.0000227 AC: 2 AN: 87996

Other (OTH) AF: 0.000272 AC: 2 AN: 7358

GnomAD4 genome AF: 0.0000736 AC: 2 AN: 27172 Hom.: 1 Cov.: 0 AF XY: 0.000152 AC XY: 2 AN XY: 13130

African (AFR) AF: 0.000143 AC: 2 AN: 13980

American (AMR) AF: 0.00 AC: 0 AN: 1744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 300

East Asian (EAS) AF: 0.00 AC: 0 AN: 512

South Asian (SAS) AF: 0.00 AC: 0 AN: 672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1496

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8052

Other (OTH) AF: 0.00 AC: 0 AN: 326

Alfa AF: 0.715 Hom.: 17851

Asia WGS AF: 0.866 AC: 3011 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.75
DANN	Benign	0.86
PhyloP100		-0.51
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs385440;

hg19: chr22-18901090;

COSMIC: COSV58231100;

COSMIC: COSV58231100;