2-189666493-T-C

Variant names:

• chr2-189666493-T-C
• NM_019048.4:c.361T>C

Variant summary

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

The NM_019048.4(ASNSD1):​c.361T>C​(p.Phe121Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 31)
• Consequence: ASNSD1 NM_019048.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASNSD1	NM_019048.4	c.361T>C	p.Phe121Leu	missense_variant	Exon 4 of 6	ENST00000260952.9	NP_061921.2
ASNSD1	NM_001353497.2	c.361T>C	p.Phe121Leu	missense_variant	Exon 3 of 5		NP_001340426.1
ASDURF	NM_001353493.2	c.*382T>C		downstream_gene_variant		ENST00000607829.6	NP_001340422.1
ASDURF	NM_001353494.2	c.*435T>C		downstream_gene_variant			NP_001340423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASNSD1	ENST00000260952.9	c.361T>C	p.Phe121Leu	missense_variant	Exon 4 of 6	1	NM_019048.4	ENSP00000260952.4
ENSG00000286165	ENST00000606910.5	c.221-703T>C		intron_variant	Intron 3 of 4	3		ENSP00000476091.1
ASDURF	ENST00000607829.6	c.*382T>C		downstream_gene_variant		2	NM_001353493.2	ENSP00000475224.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361T>C (p.F121L) alteration is located in exon 4 (coding exon 1) of the ASNSD1 gene. This alteration results from a T to C substitution at nucleotide position 361, causing the phenylalanine (F) at amino acid position 121 to be replaced by a leucine (L). 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	0.79
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.066	T;T
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.80		Loss of catalytic residue at F121 (P = 0.2643);Loss of catalytic residue at F121 (P = 0.2643);
MVP		0.35
MPC		0.49
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.83

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: chr2-190531219;