chr7-97868955-G-T

Variant names:

• chr7-97868955-G-T
• rs1554350554
• NM_001673.5:c.202C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_001673.5(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 NM_001673.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.99
• Publications: 0 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: Likely_pathogenic. The variant received 7 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, 5 uncertain in NM_001673.5
• 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 7-97868955-G-T is Pathogenic according to our data. Variant chr7-97868955-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522653.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASNS	NM_001673.5	MANE Select	c.202C>A	p.Pro68Thr	missense	Exon 3 of 13	NP_001664.3
	ASNS	NM_001352496.2		c.202C>A	p.Pro68Thr	missense	Exon 4 of 14	NP_001339425.1
	ASNS	NM_133436.3		c.202C>A	p.Pro68Thr	missense	Exon 3 of 13	NP_597680.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASNS	ENST00000394308.8	TSL:1 MANE Select	c.202C>A	p.Pro68Thr	missense	Exon 3 of 13	ENSP00000377845.3
	ASNS	ENST00000175506.8	TSL:1	c.202C>A	p.Pro68Thr	missense	Exon 4 of 14	ENSP00000175506.4
	ASNS	ENST00000931349.1		c.202C>A	p.Pro68Thr	missense	Exon 3 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: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.21	T
Polyphen		0.88	P
Vest4		0.79
MutPred		0.50		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
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs1554350554; hg19: chr7-97498267;