rs11575292

Variant names:

• chr7-50543903-C-A
• rs11575292
• NM_001082971.2:c.183G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-50543903-C-A
• chr7-50543903-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 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. 13/21 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:4
• Conservation: PhyloP100: 0.0320
• Publications: 5 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 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, 9 uncertain in NM_001082971.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.40928 (below the threshold of 3.09). Trascript score misZ: 1.0771 (below the threshold of 3.09). GenCC associations: The gene is linked to aromatic L-amino acid decarboxylase deficiency.
• 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082971.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDC	NM_001082971.2	MANE Select	c.183G>T	p.Glu61Asp	missense	Exon 2 of 15	NP_001076440.2	A0A0S2Z3N4
	DDC	NM_000790.4		c.183G>T	p.Glu61Asp	missense	Exon 2 of 15	NP_000781.2	P20711-1
	DDC	NM_001242886.2		c.183G>T	p.Glu61Asp	missense	Exon 2 of 14	NP_001229815.2	A0A087WV24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDC	ENST00000444124.7	TSL:1 MANE Select	c.183G>T	p.Glu61Asp	missense	Exon 2 of 15	ENSP00000403644.2	P20711-1
	DDC	ENST00000357936.9	TSL:1	c.183G>T	p.Glu61Asp	missense	Exon 2 of 15	ENSP00000350616.5	P20711-1
	DDC	ENST00000380984.4	TSL:1	c.183G>T	p.Glu61Asp	missense	Exon 2 of 10	ENSP00000370371.4	P20711-2

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

GnomAD2 exomes AF: 0.00121 AC: 303 AN: 251314 AF XY: 0.000847

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 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

African (AFR) AF: 0.0185 AC: 618 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112004

Other (OTH) AF: 0.000861 AC: 52 AN: 60394

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

African (AFR) AF: 0.0171 AC: 709 AN: 41560

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.0228 Hom.: 3204

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of aromatic-L-amino-acid decarboxylase (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.032
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.071
Sift	Benign	0.066	T
Sift4G	Benign	0.16	T
Polyphen		0.012	B
Vest4		0.30
MutPred		0.31		Loss of methylation at K62 (P = 0.0842)
MVP		0.49
MPC		0.27
ClinPred		0.022	T
GERP RS		0.81
PromoterAI		-0.066	Neutral
Varity_R		0.30
gMVP		0.87
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

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