chr7-122079654-T-G

Position:

chr7-122079654-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_005763.4(AASS):c.2339A>C(p.Lys780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,080 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

AASS
NM_005763.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.669

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]

AASS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a modified_residue N6-acetyllysine (size 0) in uniprot entity AASS_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.07500717).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000926 (141/152310) while in subpopulation NFE AF= 0.00157 (107/68034). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AASS	NM_005763.4 linkuse as main transcript	c.2339A>C	p.Lys780Thr	missense_variant	21/24	ENST00000417368.7	NP_005754.2
AASS	XM_011515725.3 linkuse as main transcript	c.2243A>C	p.Lys748Thr	missense_variant	20/23		XP_011514027.1
AASS	XM_047419710.1 linkuse as main transcript	c.2339A>C	p.Lys780Thr	missense_variant	21/22		XP_047275666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AASS	ENST00000417368.7 linkuse as main transcript	c.2339A>C	p.Lys780Thr	missense_variant	21/24	1	NM_005763.4	ENSP00000403768	P1

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000792

AC:

199

AN:

251370

Hom.:

AF XY:

0.000743

AC XY:

101

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00138

AC:

2011

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

927

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00142

Gnomad4 NFE exome

AF:

0.00164

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152310

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AASS protein function. 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. ClinVar contains an entry for this variant (Variation ID: 1220244). This variant has not been reported in the literature in individuals affected with AASS-related conditions. This variant is present in population databases (rs147475291, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 780 of the AASS protein (p.Lys780Thr). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Hyperlysinemia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.86

.;D

M_CAP

Benign

0.0061

MetaRNN

Benign

0.075

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.13

Sift

Benign

0.080

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.72

P;P

Vest4

0.55

MVP

0.48

MPC

0.20

ClinPred

0.11

GERP RS

3.5

Varity_R

0.24

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over