rs11575377

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000444124.7(DDC):c.717G>T(p.Met239Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,612,548 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. M239L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 14 hom. )

Consequence

DDC
ENST00000444124.7 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.482

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011080354).

BP6

Variant 7-50504057-C-A is Benign according to our data. Variant chr7-50504057-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 791009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-50504057-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDC	NM_001082971.2 linkuse as main transcript	c.717G>T	p.Met239Ile	missense_variant, splice_region_variant	7/15	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7 linkuse as main transcript	c.717G>T	p.Met239Ile	missense_variant, splice_region_variant	7/15	1	NM_001082971.2	ENSP00000403644	P1	P20711-1

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

330

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00223

AC:

560

AN:

251444

Hom.:

AF XY:

0.00213

AC XY:

289

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00670

Gnomad NFE exome

AF:

0.00335

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00171

AC:

2498

AN:

1460270

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1316

AN XY:

726588

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00595

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152278

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.00335

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00271

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00247

AC:

300

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

DDC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

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

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

DDC: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

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

Eigen

Benign

0.039

Eigen_PC

Benign

0.077

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.94

.;D;T;D;.;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.0096

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

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

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

1.1

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

REVEL

Benign

0.14

Sift

Uncertain

0.0090

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

Sift4G

Benign

0.11

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

Polyphen

0.0

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

Vest4

0.25

MutPred

0.11

Gain of loop (P = 0.2045);.;.;.;.;.;Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);

MVP

0.52

MPC

0.31

ClinPred

0.078

GERP RS

3.9

Varity_R

0.27

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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