chr7-122077984-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005763.4(AASS):​c.2516G>A​(p.Arg839Lys) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AASS
NM_005763.4 missense

Scores

4
5
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.47
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AASSNM_005763.4 linkuse as main transcriptc.2516G>A p.Arg839Lys missense_variant 23/24 ENST00000417368.7 NP_005754.2
AASSXM_011515725.3 linkuse as main transcriptc.2420G>A p.Arg807Lys missense_variant 22/23 XP_011514027.1
AASSXM_047419710.1 linkuse as main transcriptc.*24G>A 3_prime_UTR_variant 22/22 XP_047275666.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AASSENST00000417368.7 linkuse as main transcriptc.2516G>A p.Arg839Lys missense_variant 23/241 NM_005763.4 ENSP00000403768 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 05, 2022This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1405832). This variant has not been reported in the literature in individuals affected with AASS-related conditions. This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 839 of the AASS protein (p.Arg839Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T;T
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.79
.;T
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Benign
-0.67
T
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-2.0
N;N
REVEL
Benign
0.26
Sift
Benign
0.057
T;T
Sift4G
Benign
0.061
T;T
Polyphen
0.95
P;P
Vest4
0.89
MutPred
0.63
Gain of ubiquitination at R839 (P = 0.023);Gain of ubiquitination at R839 (P = 0.023);
MVP
0.59
MPC
0.63
ClinPred
0.91
D
GERP RS
5.6
Varity_R
0.81
gMVP
0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-121718038; API