7-122093136-G-T

Position:

• chr7-122093136-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The ENST00000417368.7(AASS):​c.1678C>A​(p.Pro560Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P560S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AASS ENST00000417368.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69

Genes affected

AASS (HGNC:17366): (aminoadipate-semialdehyde synthase) This gene encodes a bifunctional enzyme that catalyzes the first two steps in the mammalian lysine degradation pathway. The N-terminal and the C-terminal portions of this enzyme contain lysine-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Mutations in this gene are associated with familial hyperlysinemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-122093136-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AASS	NM_005763.4	c.1678C>A	p.Pro560Thr	missense_variant	16/24	ENST00000417368.7	NP_005754.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AASS	ENST00000417368.7	c.1678C>A	p.Pro560Thr	missense_variant	16/24	1	NM_005763.4	ENSP00000403768	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.41
Sift	Benign	0.76	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.80	P;P
Vest4		0.87
MutPred		0.49		Gain of ubiquitination at K564 (P = 0.1832);Gain of ubiquitination at K564 (P = 0.1832);
MVP		0.73
MPC		0.66
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.39
gMVP		0.76

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: rs74882337; hg19: chr7-121733190;