7-97852324-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001673.5(ASNS):c.1621T>A(p.Trp541Arg) variant causes a missense change. 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: 33)
• Consequence: ASNS NM_001673.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001673.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASNS	NM_001673.5	c.1621T>A	p.Trp541Arg	missense_variant	13/13	ENST00000394308.8
CZ1P-ASNS	NR_147989.1	n.3324T>A		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASNS	ENST00000394308.8	c.1621T>A	p.Trp541Arg	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

Aug 23, 2022

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. 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 expected to disrupt ASNS protein function. This variant has not been reported in the literature in individuals affected with ASNS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 541 of the ASNS protein (p.Trp541Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;.;D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;.;.;.;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.8	H;H;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;.
Vest4		0.88
MutPred		0.74		Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);.;Gain of disorder (P = 0.0092);.;.;.;
MVP		0.81
MPC		1.7
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.94
gMVP		0.95

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: chr7-97481636;