4-170060960-C-A

Position:

• chr4-170060960-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016228.4(AADAT):​c.1246G>T​(p.Val416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000797 in 1,380,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: AADAT NM_016228.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

AADAT (HGNC:17929): (aminoadipate aminotransferase) This gene encodes a protein that is highly similar to mouse and rat kynurenine aminotransferase II. The rat protein is a homodimer with two transaminase activities. One activity is the transamination of alpha-aminoadipic acid, a final step in the saccaropine pathway which is the major pathway for L-lysine catabolism. The other activity involves the transamination of kynurenine to produce kynurenine acid, the precursor of kynurenic acid which has neuroprotective properties. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09891194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AADAT	NM_016228.4	c.1246G>T	p.Val416Leu	missense_variant	13/13	ENST00000337664.9	NP_057312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AADAT	ENST00000337664.9	c.1246G>T	p.Val416Leu	missense_variant	13/13	1	NM_016228.4	ENSP00000336808	P3
AADAT	ENST00000509167.5	c.1258G>T	p.Val420Leu	missense_variant	14/14	1		ENSP00000423190	A1
AADAT	ENST00000515480.5	c.1246G>T	p.Val416Leu	missense_variant	14/14	1		ENSP00000423341	P3
AADAT	ENST00000353187.6	c.1246G>T	p.Val416Leu	missense_variant	14/14	2		ENSP00000226840	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000797 AC: 11 AN: 1380676 Hom.: 0 Cov.: 28 AF XY: 0.0000103 AC XY: 7 AN XY: 681302

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: 0.00000841

Gnomad4 OTH exome AF: 0.0000349

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.1246G>T (p.V416L) alteration is located in exon 13 (coding exon 13) of the AADAT gene. This alteration results from a G to T substitution at nucleotide position 1246, causing the valine (V) at amino acid position 416 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	T;.;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.87	.;D;.;D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.099	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.60	N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.70	N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.064	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.14
MutPred		0.64		Gain of disorder (P = 0.109);.;Gain of disorder (P = 0.109);Gain of disorder (P = 0.109);
MVP		0.26
MPC		0.84
ClinPred		0.31	T
GERP RS		1.4
Varity_R		0.16
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr4-170982111;