7-97854653-C-G

Position:

• chr7-97854653-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 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).

• 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

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]

ENSG00000284707 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 545473.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASNS	NM_001673.5	c.1165G>C	p.Glu389Gln	missense_variant	10/13	ENST00000394308.8	NP_001664.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASNS	ENST00000394308.8	c.1165G>C	p.Glu389Gln	missense_variant	10/13	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

Likely pathogenic, no assertion criteria provided

clinical testing

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

Mar 31, 2018

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;.;.;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs948326794; hg19: chr7-97483965;