7-50463289-C-T

Position:

chr7-50463289-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_001082971.2(DDC):c.1385G>A(p.Arg462Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,614,172 control chromosomes in the GnomAD database, including 1,143 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R462P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.052 ( 478 hom., cov: 32)

Exomes 𝑓: 0.019 ( 665 hom. )

Consequence

DDC
NM_001082971.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.227

Variant links:

Genes affected

DDC (HGNC:2719): (dopa decarboxylase) The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2011]

DDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-50463289-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2136536.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012446344).

BP6

Variant 7-50463289-C-T is Benign according to our data. Variant chr7-50463289-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 360429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-50463289-C-T is described in Lovd as [Benign]. Variant chr7-50463289-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDC	NM_001082971.2 linkuse as main transcript	c.1385G>A	p.Arg462Gln	missense_variant	14/15	ENST00000444124.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDC	ENST00000444124.7 linkuse as main transcript	c.1385G>A	p.Arg462Gln	missense_variant	14/15	1	NM_001082971.2	P1	P20711-1

Frequencies

GnomAD3 genomes

AF:

0.0522

AC:

7944

AN:

152208

Hom.:

474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0283

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00857

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0378

GnomAD3 exomes

AF:

0.0227

AC:

5712

AN:

251162

Hom.:

208

AF XY:

0.0208

AC XY:

2822

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.00869

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0190

AC:

27816

AN:

1461846

Hom.:

665

Cov.:

AF XY:

0.0185

AC XY:

13428

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.155

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.00846

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0143

Gnomad4 FIN exome

AF:

0.00942

Gnomad4 NFE exome

AF:

0.0166

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0524

AC:

7978

AN:

152326

Hom.:

478

Cov.:

AF XY:

0.0504

AC XY:

3755

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.147

Gnomad4 AMR

AF:

0.0283

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00857

Gnomad4 NFE

AF:

0.0169

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0204

Hom.:

192

Bravo

AF:

0.0574

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.151

AC:

664

ESP6500EA

AF:

0.0149

AC:

128

ExAC

AF:

0.0263

AC:

3192

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 31177555, 30911067) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Deficiency of aromatic-L-amino-acid decarboxylase

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

DDC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.022

DANN

Benign

0.91

DEOGEN2

Benign

0.10

T;.;T;.;.;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.027

LIST_S2

Uncertain

0.86

.;D;D;D;.;D;D

MetaRNN

Benign

0.0012

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;.;.;.;.;.;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.23

N;.;.;.;N;N;N

REVEL

Benign

0.020

Sift

Benign

0.14

T;.;.;.;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.;B

Vest4

0.012

MPC

0.33

ClinPred

0.00045

GERP RS

-4.2

Varity_R

0.053

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over