7-50537928-C-T

Position:

chr7-50537928-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_001082971.2(DDC):c.367G>A(p.Gly123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

DDC
NM_001082971.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.09

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:

DDC-AS1 (HGNC:40171): (DDC antisense RNA 1)

DDC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a region_of_interest 2 X approximate tandem repeats (size 120) in uniprot entity DDC_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_001082971.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 7-50537928-C-T is Pathogenic according to our data. Variant chr7-50537928-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1036808.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-50537928-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDC	NM_001082971.2 link	c.367G>A	p.Gly123Arg	missense_variant	4/15	ENST00000444124.7	NP_001076440.2	P20711-1Q53Y41A0A0S2Z3N4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7 link	c.367G>A	p.Gly123Arg	missense_variant	4/15	1	NM_001082971.2	ENSP00000403644.2		P20711-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249826

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461298

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 123 of the DDC protein (p.Gly123Arg). This variant is present in population databases (rs768596169, gnomAD 0.003%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 20505134, 32369189). ClinVar contains an entry for this variant (Variation ID: 1036808). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DDC protein function. Experimental studies have shown that this missense change affects DDC function (PMID: 24865461). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.97

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

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

2.0

M;M;.;.;M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.5

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

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;T

Polyphen

1.0

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

Vest4

0.91

MutPred

0.81

Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);.;Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);Gain of MoRF binding (P = 0.086);

MVP

0.76

MPC

1.1

ClinPred

0.99

GERP RS

5.6

Varity_R

0.97

gMVP

0.99

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