rs146648839

chr22-18936116-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016335.6(PRODH):c.172G>A(p.Ala58Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. A58A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Failed GnomAD Quality Control
• Consequence: PRODH NM_016335.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018523335).
• BP6: Variant 22-18936116-C-T is Benign according to our data. Variant chr22-18936116-C-T is described in ClinVar as [Benign]. Clinvar id is 459914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRODH	NM_016335.6	c.172G>A	p.Ala58Thr	missense_variant	1/14	ENST00000357068.11
PRODH	NM_001195226.2	c.-52+274G>A		intron_variant
PRODH	NM_001368250.2	c.-52+54G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRODH	ENST00000357068.11	c.172G>A	p.Ala58Thr	missense_variant	1/14	1	NM_016335.6	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 FAILED QC

GnomAD3 exomes AF: 0.0188 AC: 1324 AN: 70306 Hom.: 21 AF XY: 0.0174 AC XY: 713 AN XY: 40932

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00482

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0441

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Alfa AF: 0.0132 Hom.: 2

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.0296 AC: 45

ESP6500EA AF: 0.0120 AC: 37

ExAC AF: 0.00606 AC: 184

Asia WGS AF: 0.00726 AC: 25 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 20524212, 24842239) -

Proline dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.053
Dann	Benign	0.96
DEOGEN2	Benign	0.0018	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.64	T;.
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Pathogenic	0.88	D
Sift4G	Benign	1.0	T;T
Vest4		0.017
MPC		0.27
ClinPred		0.0054	T
GERP RS		-4.3
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs146648839; hg19: chr22-18923629; COSMIC: COSV100472333; COSMIC: COSV100472333;