7-50476616-C-T

Variant names:

• chr7-50476616-C-T
• rs4490786
• NM_001082971.2:c.1041+8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001082971.2(DDC):​c.1041+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,608,232 control chromosomes in the GnomAD database, including 36,358 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3562 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32796 hom.)
• Consequence: DDC NM_001082971.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003647
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.166
• Publications: 20 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-50476616-C-T is Benign according to our data. Variant chr7-50476616-C-T is described in ClinVar as Benign. ClinVar VariationId is 360432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDC	NM_001082971.2	c.1041+8G>A		splice_region_variant, intron_variant	Intron 11 of 14	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7	c.1041+8G>A		splice_region_variant, intron_variant	Intron 11 of 14	1	NM_001082971.2	ENSP00000403644.2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32317 AN: 151990 Hom.: 3558 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.209 AC: 52149 AN: 249656 AF XY: 0.208

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.210 AC: 306046 AN: 1456124 Hom.: 32796 Cov.: 31 AF XY: 0.210 AC XY: 151883 AN XY: 724660

African (AFR) AF: 0.224 AC: 7457 AN: 33352

American (AMR) AF: 0.243 AC: 10863 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4932 AN: 26096

East Asian (EAS) AF: 0.164 AC: 6522 AN: 39680

South Asian (SAS) AF: 0.196 AC: 16870 AN: 86128

European-Finnish (FIN) AF: 0.258 AC: 13694 AN: 53020

Middle Eastern (MID) AF: 0.206 AC: 1186 AN: 5764

European-Non Finnish (NFE) AF: 0.210 AC: 232360 AN: 1107174

Other (OTH) AF: 0.202 AC: 12162 AN: 60204

GnomAD4 genome AF: 0.213 AC: 32328 AN: 152108 Hom.: 3562 Cov.: 32 AF XY: 0.216 AC XY: 16077 AN XY: 74340

African (AFR) AF: 0.223 AC: 9258 AN: 41486

American (AMR) AF: 0.212 AC: 3233 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3468

East Asian (EAS) AF: 0.144 AC: 744 AN: 5172

South Asian (SAS) AF: 0.188 AC: 904 AN: 4820

European-Finnish (FIN) AF: 0.267 AC: 2820 AN: 10572

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14003 AN: 67986

Other (OTH) AF: 0.196 AC: 414 AN: 2114

Alfa AF: 0.204 Hom.: 4912

Bravo AF: 0.211

Asia WGS AF: 0.142 AC: 495 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.194

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not specified Benign:2

Oct 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 38. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.3
DANN	Benign	0.66
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4490786; hg19: chr7-50544314; COSMIC: COSV63564462;