chr7-97852307-G-T

Variant names:

• chr7-97852307-G-T
• rs897877891
• NM_001673.5:c.1638C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001673.5(ASNS):​c.1638C>A​(p.Asp546Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ASNS NM_001673.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ENSG00000284707 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

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.1638C>A	p.Asp546Glu	missense	Exon 13 of 13	NP_001664.3
	ASNS	NM_001352496.2		c.1638C>A	p.Asp546Glu	missense	Exon 14 of 14	NP_001339425.1	P08243-1
	ASNS	NM_133436.3		c.1638C>A	p.Asp546Glu	missense	Exon 13 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.1638C>A	p.Asp546Glu	missense	Exon 13 of 13	ENSP00000377845.3	P08243-1
	ASNS	ENST00000175506.8	TSL:1	c.1638C>A	p.Asp546Glu	missense	Exon 14 of 14	ENSP00000175506.4	P08243-1
	ASNS	ENST00000931349.1		c.1686C>A	p.Asp562Glu	missense	Exon 13 of 13	ENSP00000601408.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.35
Sift	Benign	0.060	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.79		Gain of MoRF binding (P = 0.1076)
MVP		0.71
MPC		1.2
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.25
gMVP		0.78
Mutation Taster		=37/63	disease causing

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: rs897877891; hg19: chr7-97481619;