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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASNS	NM_001673.5	c.1165G>C	p.Glu389Gln	missense_variant	Exon 10 of 13	ENST00000394308.8	NP_001664.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASNS	ENST00000394308.8	c.1165G>C	p.Glu389Gln	missense_variant	Exon 10 of 13	1	NM_001673.5	ENSP00000377845.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome Pathogenic:1

Mar 31, 2018

Pfaffle Lab, University Hospital for Children and Adolescents, University of Leipzig

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.1165G>C variant was observed in a compound heterozygote mode of inheritance together with the variant c.601delA in ASNS in 1 German family with microcephaly. The variants segregated in the family and were absent from large population studies and controls. The parents and the son were healthy, two daughters were affected with microcephaly. -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.;.;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	M;M;.;M;.;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;N;D;D;N;D
REVEL	Benign	0.27
Sift	Benign	0.035	D;D;D;D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;D;.;.;.
Vest4		0.41
MutPred		0.67		Loss of ubiquitination at K385 (P = 0.0642);Loss of ubiquitination at K385 (P = 0.0642);.;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;