rs11575377

chr7-50504057-C-Achr7-50504057-C-T

Variant summary

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

The NM_001082971.2(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. 13/20 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. M239L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (14 hom.)
• Consequence: DDC NM_001082971.2 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.482

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]

ACMG classification

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 GnomAd at 3 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152160 Hom.: 3 Cov.: 33

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.: 2 AF XY: 0.00213 AC XY: 289 AN XY: 135900

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.: 14 Cov.: 29 AF XY: 0.00181 AC XY: 1316 AN XY: 726588

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.: 3 Cov.: 33 AF XY: 0.00205 AC XY: 153 AN XY: 74458

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.: 3

Bravo AF: 0.00118

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00247 AC: 300

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	Jan 29, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

DDC: BP4, BS2 -

DDC-related condition Benign:1

Likely benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	15
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	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;.;.;.;.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs11575377; hg19: chr7-50571755;