7-97854653-C-G

Variant names:

• chr7-97854653-C-G
• rs948326794
• NM_001673.5:c.1165G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001673.5(ASNS):​c.1165G>C​(p.Glu389Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E389A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASNS NM_001673.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.88
• Publications: 5 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ENSG00000284707 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 7-97854653-C-G is Pathogenic according to our data. Variant chr7-97854653-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545473.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1165G>C	p.Glu389Gln	missense	Exon 10 of 13	NP_001664.3
	ASNS	NM_001352496.2		c.1165G>C	p.Glu389Gln	missense	Exon 11 of 14	NP_001339425.1	P08243-1
	ASNS	NM_133436.3		c.1165G>C	p.Glu389Gln	missense	Exon 10 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.1165G>C	p.Glu389Gln	missense	Exon 10 of 13	ENSP00000377845.3	P08243-1
	ASNS	ENST00000175506.8	TSL:1	c.1165G>C	p.Glu389Gln	missense	Exon 11 of 14	ENSP00000175506.4	P08243-1
	ASNS	ENST00000931349.1		c.1213G>C	p.Glu405Gln	missense	Exon 10 of 13	ENSP00000601408.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.27
Sift	Benign	0.035	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.41
MutPred		0.67		Loss of ubiquitination at K385 (P = 0.0642)
MVP		0.61
MPC		0.78
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.73
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs948326794; hg19: chr7-97483965;