chr4-170064788-A-T

Position:

• chr4-170064788-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016228.4(AADAT):​c.1065T>A​(p.Phe355Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AADAT NM_016228.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AADAT	NM_016228.4	c.1065T>A	p.Phe355Leu	missense_variant	11/13	ENST00000337664.9	NP_057312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AADAT	ENST00000337664.9	c.1065T>A	p.Phe355Leu	missense_variant	11/13	1	NM_016228.4	ENSP00000336808.4
AADAT	ENST00000509167.5	c.1077T>A	p.Phe359Leu	missense_variant	12/14	1		ENSP00000423190.1
AADAT	ENST00000515480.5	c.1065T>A	p.Phe355Leu	missense_variant	12/14	1		ENSP00000423341.1
AADAT	ENST00000353187.6	c.1065T>A	p.Phe355Leu	missense_variant	12/14	2		ENSP00000226840.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 09, 2023

The c.1065T>A (p.F355L) alteration is located in exon 11 (coding exon 11) of the AADAT gene. This alteration results from a T to A substitution at nucleotide position 1065, causing the phenylalanine (F) at amino acid position 355 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	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;D
Eigen	Benign	0.11
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.92	.;D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.8	H;.;H;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.79
MutPred		0.86		Gain of MoRF binding (P = 0.1826);.;Gain of MoRF binding (P = 0.1826);Gain of MoRF binding (P = 0.1826);
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		-0.69
Varity_R		0.89
gMVP		0.94

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: chr4-170985939;