rs11575292

chr7-50543903-C-Achr7-50543903-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001082971.2(DDC):c.183G>T(p.Glu61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,614,176 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (6 hom.)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0320

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001082971.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009585321).
• BP6: Variant 7-50543903-C-A is Benign according to our data. Variant chr7-50543903-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 235306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00479 (730/152304) while in subpopulation AFR AF= 0.0171 (709/41560). AF 95% confidence interval is 0.016. There are 7 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDC	NM_001082971.2	c.183G>T	p.Glu61Asp	missense_variant	2/15	ENST00000444124.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDC	ENST00000444124.7	c.183G>T	p.Glu61Asp	missense_variant	2/15	1	NM_001082971.2	P1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 729 AN: 152186 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00121 AC: 303 AN: 251314 Hom.: 2 AF XY: 0.000847 AC XY: 115 AN XY: 135850

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461872 Hom.: 6 Cov.: 31 AF XY: 0.000432 AC XY: 314 AN XY: 727232

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00479 AC: 730 AN: 152304 Hom.: 7 Cov.: 33 AF XY: 0.00465 AC XY: 346 AN XY: 74472

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.0281 Hom.: 3199

Bravo AF: 0.00521

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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	Invitae	Feb 01, 2024	- -
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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;T;.;.;.;D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;.;.;.;N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.066	T;.;.;.;T;D;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T;T
Polyphen		0.012	B;.;.;.;.;.;B;.
Vest4		0.30
MutPred		0.31		Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);Loss of methylation at K62 (P = 0.0842);
MVP		0.49
MPC		0.27
ClinPred		0.022	T
GERP RS		0.81
Varity_R		0.30
gMVP		0.87

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

Other links and lift over

dbSNP: rs11575292; hg19: chr7-50611601; COSMIC: COSV99058841; COSMIC: COSV99058841;