rs1554350554

Positions:

• chr7-97868955-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The ENST00000394308.8(ASNS):​c.202C>A​(p.Pro68Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P68L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASNS ENST00000394308.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.99

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]

CZ1P-ASNS (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000394308.8
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-97868955-G-T is Pathogenic according to our data. Variant chr7-97868955-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522653.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASNS	NM_001673.5	c.202C>A	p.Pro68Thr	missense_variant	3/13	ENST00000394308.8	NP_001664.3
CZ1P-ASNS	NR_147989.1	n.1831C>A		non_coding_transcript_exon_variant	9/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASNS	ENST00000394308.8	c.202C>A	p.Pro68Thr	missense_variant	3/13	1	NM_001673.5	ENSP00000377845	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D;.;.;T;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;.;.;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T;.;.;.;T
Polyphen		0.88	P;P;P;.;.;.;.;.;.
Vest4		0.79
MutPred		0.50		Loss of methylation at K65 (P = 0.1188);Loss of methylation at K65 (P = 0.1188);Loss of methylation at K65 (P = 0.1188);.;.;Loss of methylation at K65 (P = 0.1188);Loss of methylation at K65 (P = 0.1188);Loss of methylation at K65 (P = 0.1188);.;
MVP		0.72
MPC		1.2
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.84
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs1554350554; hg19: chr7-97498267;