7-50463289-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5PP2BP4_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. 15/21 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

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

aromatic L-amino acid decarboxylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

DDC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 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 VariationId is 2136536.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.40928 (below the threshold of 3.09). Trascript score misZ: 1.0771 (below the threshold of 3.09). GenCC associations: The gene is linked to aromatic L-amino acid decarboxylase deficiency.

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 Benign/Likely_benign. ClinVar VariationId is 360429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
DDC	NM_001082971.2 link	c.1385G>A	p.Arg462Gln	missense_variant	Exon 14 of 15	ENST00000444124.7	NP_001076440.2	P20711-1Q53Y41A0A0S2Z3N4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7 link	c.1385G>A	p.Arg462Gln	missense_variant	Exon 14 of 15	1	NM_001082971.2	ENSP00000403644.2		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

GnomAD2 exomes

AF:

0.0227

AC:

5712

AN:

251162

AF XY:

0.0208

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 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

African (AFR)

AF:

0.155

AC:

5198

AN:

33478

American (AMR)

AF:

0.0136

AC:

606

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0143

AC:

1231

AN:

86248

European-Finnish (FIN)

AF:

0.00942

AC:

503

AN:

53418

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0166

AC:

18505

AN:

1111992

Other (OTH)

AF:

0.0243

AC:

1465

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1488

2975

4463

5950

7438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

754

1508

2262

3016

3770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0524

AC:

7978

AN:

152326

Hom.:

478

Cov.:

AF XY:

0.0504

AC XY:

3755

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.147

AC:

6110

AN:

41554

American (AMR)

AF:

0.0283

AC:

433

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00779

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0141

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00857

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1151

AN:

68036

Other (OTH)

AF:

0.0374

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

357

715

1072

1430

1787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0255

Hom.:

600

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

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31177555, 30911067) -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of aromatic-L-amino-acid decarboxylase

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DDC-related disorder

Benign:1

Nov 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.23

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over