7-97853071-C-T

Variant names:

• chr7-97853071-C-T
• rs772079299
• NM_001673.5:c.1465G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001673.5(ASNS):​c.1465G>A​(p.Val489Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,579,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V489F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ASNS NM_001673.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.0240
• Publications: 1 publications found

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]

ASNS Gene-Disease associations (from GenCC):

• congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ENSG00000284707 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.8574 (below the threshold of 3.09). Trascript score misZ: 2.3971 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.023894519).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001673.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASNS	NM_001673.5	MANE Select	c.1465G>A	p.Val489Ile	missense	Exon 12 of 13	NP_001664.3
	ASNS	NM_001352496.2		c.1465G>A	p.Val489Ile	missense	Exon 13 of 14	NP_001339425.1	P08243-1
	ASNS	NM_133436.3		c.1465G>A	p.Val489Ile	missense	Exon 12 of 13	NP_597680.2	P08243-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASNS	ENST00000394308.8	TSL:1 MANE Select	c.1465G>A	p.Val489Ile	missense	Exon 12 of 13	ENSP00000377845.3	P08243-1
	ASNS	ENST00000175506.8	TSL:1	c.1465G>A	p.Val489Ile	missense	Exon 13 of 14	ENSP00000175506.4	P08243-1
	ASNS	ENST00000931349.1		c.1513G>A	p.Val505Ile	missense	Exon 12 of 13	ENSP00000601408.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 24 AN: 224098 AF XY: 0.000107

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000249 AC: 355 AN: 1427102 Hom.: 0 Cov.: 31 AF XY: 0.000237 AC XY: 168 AN XY: 707580

African (AFR) AF: 0.0000317 AC: 1 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 36588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24228

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80122

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.000312 AC: 343 AN: 1098096

Other (OTH) AF: 0.000153 AC: 9 AN: 58910

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.4
DANN	Benign	0.32
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N
PhyloP100		-0.024
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.027
Sift	Benign	0.56	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.20
MPC		0.33
ClinPred		0.018	T
GERP RS		-0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.27
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs772079299; hg19: chr7-97482383; COSMIC: COSV99446918; COSMIC: COSV99446918;