4-170066477-C-G

Position:

• chr4-170066477-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016228.4(AADAT):​c.964G>C​(p.Val322Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AADAT NM_016228.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008986
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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]

LOC107986326 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38562816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AADAT	NM_016228.4	c.964G>C	p.Val322Leu	missense_variant, splice_region_variant	10/13	ENST00000337664.9	NP_057312.1
LOC107986326	XR_001741918.2	n.306C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AADAT	ENST00000337664.9	c.964G>C	p.Val322Leu	missense_variant, splice_region_variant	10/13	1	NM_016228.4	ENSP00000336808	P3
AADAT	ENST00000509167.5	c.976G>C	p.Val326Leu	missense_variant, splice_region_variant	11/14	1		ENSP00000423190	A1
AADAT	ENST00000515480.5	c.964G>C	p.Val322Leu	missense_variant, splice_region_variant	11/14	1		ENSP00000423341	P3
AADAT	ENST00000353187.6	c.964G>C	p.Val322Leu	missense_variant, splice_region_variant	11/14	2		ENSP00000226840	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Feb 05, 2024

The c.964G>C (p.V322L) alteration is located in exon 10 (coding exon 10) of the AADAT gene. This alteration results from a G to C substitution at nucleotide position 964, causing the valine (V) at amino acid position 322 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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D;.;D;D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.4	L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.071	T;T;T;T
Polyphen		0.52	P;B;P;P
Vest4		0.41
MutPred		0.56		Loss of phosphorylation at Y326 (P = 0.1879);.;Loss of phosphorylation at Y326 (P = 0.1879);Loss of phosphorylation at Y326 (P = 0.1879);
MVP		0.82
MPC		1.0
ClinPred		0.87	D
GERP RS		3.8
Varity_R		0.46
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00090
dbscSNV1_RF	Benign	0.036
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-170987628;