7-97852327-T-C

Variant summary

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

The NM_001673.5(ASNS):c.1618A>G(p.Lys540Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASNS NM_001673.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

Genes affected

ASNS (HGNC:753): (asparagine synthetase (glutamine-hydrolyzing)) The protein encoded by this gene is involved in the synthesis of asparagine. This gene complements a mutation in the temperature-sensitive hamster mutant ts11, which blocks progression through the G1 phase of the cell cycle at nonpermissive temperature. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

CZ1P-ASNS (HGNC:):

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=0.2574137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASNS	NM_001673.5	c.1618A>G	p.Lys540Glu	missense_variant	13/13	ENST00000394308.8
CZ1P-ASNS	NR_147989.1	n.3321A>G		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASNS	ENST00000394308.8	c.1618A>G	p.Lys540Glu	missense_variant	13/13	1	NM_001673.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 540 of the ASNS protein (p.Lys540Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ASNS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.;T;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;.;.;.;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;L;.;L;.;.;.
MutationTaster	Benign	0.58	N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.11	T;T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T
Polyphen		0.079	B;B;.;B;.;.;.
Vest4		0.29
MutPred		0.49		Loss of methylation at K540 (P = 0.0012);Loss of methylation at K540 (P = 0.0012);.;Loss of methylation at K540 (P = 0.0012);.;.;.;
MVP		0.54
MPC		0.57
ClinPred		0.63	D
GERP RS		2.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.11
gMVP		0.67

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: chr7-97481639;