7-50504057-C-T

Variant names:

• chr7-50504057-C-T
• rs11575377
• NM_001082971.2:c.717G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001082971.2(DDC):​c.717G>A​(p.Met239Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M239L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DDC NM_001082971.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.482
• Publications: 7 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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.717G>A	p.Met239Ile	missense splice_region	Exon 7 of 15	NP_001076440.2	A0A0S2Z3N4
	DDC	NM_000790.4		c.717G>A	p.Met239Ile	missense splice_region	Exon 7 of 15	NP_000781.2	P20711-1
	DDC	NM_001242886.2		c.603G>A	p.Met201Ile	missense splice_region	Exon 6 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.717G>A	p.Met239Ile	missense splice_region	Exon 7 of 15	ENSP00000403644.2	P20711-1
	DDC	ENST00000357936.9	TSL:1	c.717G>A	p.Met239Ile	missense splice_region	Exon 7 of 15	ENSP00000350616.5	P20711-1
	DDC	ENST00000380984.4	TSL:1	c.717G>A	p.Met239Ile	missense splice_region	Exon 7 of 10	ENSP00000370371.4	P20711-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460284 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110554

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 4

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.039
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.48
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.14
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.11		Gain of loop (P = 0.2045)
MVP		0.52
MPC		0.31
ClinPred		0.63	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.53
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.40		Position offset: 2

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

Other links and lift over

dbSNP: rs11575377; hg19: chr7-50571755;