7-50463253-A-C

Variant names:

• chr7-50463253-A-C
• NM_001082971.2:c.1421T>G

Variant summary

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

The NM_001082971.2(DDC):​c.1421T>G​(p.Val474Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.80

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.1421T>G	p.Val474Gly	missense_variant	Exon 14 of 15	ENST00000444124.7	NP_001076440.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDC	ENST00000444124.7	c.1421T>G	p.Val474Gly	missense_variant	Exon 14 of 15	1	NM_001082971.2	ENSP00000403644.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase Uncertain:1

Dec 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 474 of the DDC protein (p.Val474Gly). This variant has not been reported in the literature in individuals affected with DDC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D;.;T;.;.;.;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	.;T;T;T;.;T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;M
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.8	D;.;.;.;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;.;.;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.57	P;.;.;.;.;.;P
Vest4		0.24
MutPred		0.73		Gain of disorder (P = 0.0168);.;.;.;.;.;Gain of disorder (P = 0.0168);
MVP		0.71
MPC		0.61
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-50530951;