2-189666550-C-T

Variant names:

• chr2-189666550-C-T
• rs1271827593
• NM_019048.4:c.418C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019048.4(ASNSD1):​c.418C>T​(p.Arg140Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000274 in 1,460,792 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ASNSD1 NM_019048.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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:):

ASDURF (HGNC:53619): (ASNSD1 upstream open reading frame) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASNSD1	NM_019048.4	c.418C>T	p.Arg140Cys	missense_variant	Exon 4 of 6	ENST00000260952.9	NP_061921.2
ASNSD1	NM_001353497.2	c.418C>T	p.Arg140Cys	missense_variant	Exon 3 of 5		NP_001340426.1
ASDURF	NM_001353493.2	c.*439C>T		downstream_gene_variant		ENST00000607829.6	NP_001340422.1
ASDURF	NM_001353494.2	c.*492C>T		downstream_gene_variant			NP_001340423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASNSD1	ENST00000260952.9	c.418C>T	p.Arg140Cys	missense_variant	Exon 4 of 6	1	NM_019048.4	ENSP00000260952.4
ENSG00000286165	ENST00000606910.5	c.221-646C>T		intron_variant	Intron 3 of 4	3		ENSP00000476091.1
ASDURF	ENST00000607829.6	c.*439C>T		downstream_gene_variant		2	NM_001353493.2	ENSP00000475224.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460792 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 726680

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: 0.0000351

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418C>T (p.R140C) 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 418, causing the arginine (R) at amino acid position 140 to be replaced by a cysteine (C). 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	0.78
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;.
Vest4		0.86
MutPred		0.68		Loss of MoRF binding (P = 0.0646);Loss of MoRF binding (P = 0.0646);
MVP		0.70
MPC		0.56
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.85
gMVP		0.92

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

Other links and lift over

dbSNP: rs1271827593; hg19: chr2-190531276; COSMIC: COSV105028676; COSMIC: COSV105028676;