chr4-170060945-T-C

Position:

• chr4-170060945-T-C

Variant summary

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

The NM_016228.4(AADAT):​c.1261A>G​(p.Ile421Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,389,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AADAT NM_016228.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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=0.24562669).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AADAT	NM_016228.4	c.1261A>G	p.Ile421Val	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.1261A>G	p.Ile421Val	missense_variant	13/13	1	NM_016228.4	ENSP00000336808.4
AADAT	ENST00000509167.5	c.1273A>G	p.Ile425Val	missense_variant	14/14	1		ENSP00000423190.1
AADAT	ENST00000515480.5	c.1261A>G	p.Ile421Val	missense_variant	14/14	1		ENSP00000423341.1
AADAT	ENST00000353187.6	c.1261A>G	p.Ile421Val	missense_variant	14/14	2		ENSP00000226840.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1389554 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 685540

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 03, 2024

The c.1261A>G (p.I421V) alteration is located in exon 13 (coding exon 13) of the AADAT gene. This alteration results from a A to G substitution at nucleotide position 1261, causing the isoleucine (I) at amino acid position 421 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;T;T
Eigen	Benign	-0.028
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.62	.;T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.84	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.42	B;P;B;B
Vest4		0.30
MutPred		0.60		Gain of disorder (P = 0.0252);.;Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);
MVP		0.42
MPC		0.75
ClinPred		0.31	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs1302880252; hg19: chr4-170982096;