2-189667010-C-T

Variant names:

• chr2-189667010-C-T
• rs1574279573
• NM_019048.4:c.878C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019048.4(ASNSD1):​c.878C>T​(p.Ala293Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASNSD1 NM_019048.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

Genes affected

ASNSD1 (HGNC:24910): (asparagine synthetase domain containing 1) Predicted to enable asparagine synthase (glutamine-hydrolyzing) activity. Predicted to be involved in asparagine biosynthetic process and glutamine metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286165 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASNSD1	NM_019048.4	c.878C>T	p.Ala293Val	missense_variant	Exon 4 of 6	ENST00000260952.9	NP_061921.2
ASNSD1	NM_001353497.2	c.878C>T	p.Ala293Val	missense_variant	Exon 3 of 5		NP_001340426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASNSD1	ENST00000260952.9	c.878C>T	p.Ala293Val	missense_variant	Exon 4 of 6	1	NM_019048.4	ENSP00000260952.4
ENSG00000286165	ENST00000606910.5	c.221-186C>T		intron_variant	Intron 3 of 4	3		ENSP00000476091.1
ASNSD1	ENST00000420250.1	c.878C>T	p.Ala293Val	missense_variant	Exon 3 of 5	5		ENSP00000406790.1
ASNSD1	ENST00000607062.5	c.22-754C>T		intron_variant	Intron 4 of 5	5		ENSP00000475970.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461622 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727116

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.878C>T (p.A293V) alteration is located in exon 4 (coding exon 1) of the ASNSD1 gene. This alteration results from a C to T substitution at nucleotide position 878, causing the alanine (A) at amino acid position 293 to be replaced by a valine (V). 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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;.
Vest4		0.42
MutPred		0.68		Gain of ubiquitination at K296 (P = 0.0797);Gain of ubiquitination at K296 (P = 0.0797);
MVP		0.43
MPC		0.52
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.27
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1574279573; hg19: chr2-190531736;