rs11575302

Positions:

• chr7-50539996-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001082971.2(DDC):​c.234C>T​(p.Ala78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,613,830 control chromosomes in the GnomAD database, including 1,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (437 hom., cov: 32)
  • Exomes 𝑓: 0.018 (599 hom.)
• Consequence: DDC NM_001082971.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.901

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

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 7-50539996-G-A is Benign according to our data. Variant chr7-50539996-G-A is described in ClinVar as [Benign]. Clinvar id is 360441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-50539996-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.901 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDC	NM_001082971.2	c.234C>T	p.Ala78=	synonymous_variant	3/15	ENST00000444124.7
DDC-AS1	NR_033845.1	n.344G>A		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDC	ENST00000444124.7	c.234C>T	p.Ala78=	synonymous_variant	3/15	1	NM_001082971.2	P1
DDC-AS1	ENST00000454521.1	n.344G>A		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7528 AN: 152140 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0430

GnomAD3 exomes AF: 0.0215 AC: 5392 AN: 250550 Hom.: 193 AF XY: 0.0196 AC XY: 2652 AN XY: 135508

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.00803

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0184 AC: 26873 AN: 1461570 Hom.: 599 Cov.: 31 AF XY: 0.0178 AC XY: 12908 AN XY: 727082

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00846

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.00892

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0226

GnomAD4 genome AF: 0.0497 AC: 7564 AN: 152260 Hom.: 437 Cov.: 32 AF XY: 0.0478 AC XY: 3559 AN XY: 74454

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0307 Hom.: 100

Bravo AF: 0.0546

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2018	- -

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	Jan 13, 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

Oct 28, 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
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.87

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: rs11575302; hg19: chr7-50607694;