chr7-122079643-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_005763.4(AASS):​c.2350C>A​(p.Leu784Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

AASS
NM_005763.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.57
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.019785374).
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000787 (115/1461774) while in subpopulation SAS AF= 0.00128 (110/86256). AF 95% confidence interval is 0.00108. There are 1 homozygotes in gnomad4_exome. There are 89 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AASSNM_005763.4 linkuse as main transcriptc.2350C>A p.Leu784Ile missense_variant 21/24 ENST00000417368.7 NP_005754.2
AASSXM_011515725.3 linkuse as main transcriptc.2254C>A p.Leu752Ile missense_variant 20/23 XP_011514027.1
AASSXM_047419710.1 linkuse as main transcriptc.2350C>A p.Leu784Ile missense_variant 21/22 XP_047275666.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AASSENST00000417368.7 linkuse as main transcriptc.2350C>A p.Leu784Ile missense_variant 21/241 NM_005763.4 ENSP00000403768 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251388
Hom.:
0
AF XY:
0.000191
AC XY:
26
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00108
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000787
AC:
115
AN:
1461774
Hom.:
1
Cov.:
31
AF XY:
0.000122
AC XY:
89
AN XY:
727194
show subpopulations
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:
0.00128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.000157
AC:
19
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 30, 2022The c.2350C>A (p.L784I) alteration is located in exon 21 (coding exon 20) of the AASS gene. This alteration results from a C to A substitution at nucleotide position 2350, causing the leucine (L) at amino acid position 784 to be replaced by an isoleucine (I). 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
0.083
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
8.0
DANN
Benign
0.86
DEOGEN2
Benign
0.21
T;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.82
.;T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.020
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.36
N;N
REVEL
Benign
0.11
Sift
Benign
0.36
T;T
Sift4G
Benign
0.37
T;T
Polyphen
0.14
B;B
Vest4
0.20
MutPred
0.55
Loss of ubiquitination at K785 (P = 0.0653);Loss of ubiquitination at K785 (P = 0.0653);
MVP
0.18
MPC
0.19
ClinPred
0.046
T
GERP RS
0.10
Varity_R
0.14
gMVP
0.34

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs546113656; hg19: chr7-121719697; API