chr7-50463289-C-T

Variant names:

• chr7-50463289-C-T
• rs11575542
• NM_001082971.2:c.1385G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001082971.2(DDC):​c.1385G>A​(p.Arg462Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,614,172 control chromosomes in the GnomAD database, including 1,143 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R462P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.052 (478 hom., cov: 32)
  • Exomes 𝑓: 0.019 (665 hom.)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.227
• Publications: 27 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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-50463289-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2136536.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=0.0012446344).
• BP6: Variant 7-50463289-C-T is Benign according to our data. Variant chr7-50463289-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

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.1385G>A	p.Arg462Gln	missense	Exon 14 of 15	NP_001076440.2	A0A0S2Z3N4
	DDC	NM_000790.4		c.1385G>A	p.Arg462Gln	missense	Exon 14 of 15	NP_000781.2	P20711-1
	DDC	NM_001242886.2		c.1271G>A	p.Arg424Gln	missense	Exon 13 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.1385G>A	p.Arg462Gln	missense	Exon 14 of 15	ENSP00000403644.2	P20711-1
	DDC	ENST00000357936.9	TSL:1	c.1385G>A	p.Arg462Gln	missense	Exon 14 of 15	ENSP00000350616.5	P20711-1
	DDC	ENST00000897740.1		c.1529G>A	p.Arg510Gln	missense	Exon 15 of 16	ENSP00000567799.1

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7944 AN: 152208 Hom.: 474 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00857

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0227 AC: 5712 AN: 251162 AF XY: 0.0208

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0190 AC: 27816 AN: 1461846 Hom.: 665 Cov.: 32 AF XY: 0.0185 AC XY: 13428 AN XY: 727220

African (AFR) AF: 0.155 AC: 5198 AN: 33478

American (AMR) AF: 0.0136 AC: 606 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00846 AC: 221 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0143 AC: 1231 AN: 86248

European-Finnish (FIN) AF: 0.00942 AC: 503 AN: 53418

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18505 AN: 1111992

Other (OTH) AF: 0.0243 AC: 1465 AN: 60396

GnomAD4 genome AF: 0.0524 AC: 7978 AN: 152326 Hom.: 478 Cov.: 32 AF XY: 0.0504 AC XY: 3755 AN XY: 74490

African (AFR) AF: 0.147 AC: 6110 AN: 41554

American (AMR) AF: 0.0283 AC: 433 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4832

European-Finnish (FIN) AF: 0.00857 AC: 91 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1151 AN: 68036

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0255 Hom.: 600

Bravo AF: 0.0574

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.151 AC: 664

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0263 AC: 3192

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Deficiency of aromatic-L-amino-acid decarboxylase (2)
-	-	2	not specified (2)
-	-	1	DDC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.022
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.027	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.23
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.020
Sift	Benign	0.14	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.33
ClinPred		0.00045	T
GERP RS		-4.2
Varity_R		0.053
gMVP		0.44
Mutation Taster		=96/4	polymorphism (auto)

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: rs11575542; hg19: chr7-50530987;