7-50504057-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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. 13/23 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 Lovd.

• 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDC	NM_001082971.2	c.717G>A	p.Met239Ile	missense_variant, splice_region_variant	Exon 7 of 15	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7	c.717G>A	p.Met239Ile	missense_variant, splice_region_variant	Exon 7 of 15	1	NM_001082971.2	ENSP00000403644.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.;.;T;.
Eigen	Benign	0.039
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.94	.;D;T;D;.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;.;.;.;.;.;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.1	N;.;.;.;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0090	D;.;.;.;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;B;.
Vest4		0.25
MutPred		0.11		Gain of loop (P = 0.2045);.;.;.;.;.;Gain of loop (P = 0.2045);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11575377; hg19: chr7-50571755;