Genetic Variant ASTL:p.Trp346Arg (chr2-96124110-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001002036.4(ASTL):c.1036T>C(p.Trp346Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,451,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ASTL
NM_001002036.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.226

Publications

0 publications found

Variant links:

Genes affected

ASTL (HGNC:31704): (astacin like metalloendopeptidase) Predicted to enable aspartic-type peptidase activity; glutamic-type peptidase activity; and metalloendopeptidase activity. Predicted to be involved in several processes, including negative regulation of binding activity of sperm to zona pellucida; positive regulation of protein processing; and prevention of polyspermy. Predicted to be located in cortical granule and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ASTL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07249886).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002036.4. 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
	ASTL	NM_001002036.4	MANE Select	c.1036T>C	p.Trp346Arg	missense	Exon 9 of 9	NP_001002036.3	Q6HA08

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASTL	ENST00000342380.3	TSL:1 MANE Select	c.1036T>C	p.Trp346Arg	missense	Exon 9 of 9	ENSP00000343674.2	Q6HA08
	ASTL	ENST00000867255.1		c.982T>C	p.Trp328Arg	missense	Exon 9 of 9	ENSP00000537314.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000821

AC:

AN:

243474

AF XY:

0.00000759

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000913

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1451332

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.00

AC:

AN:

44052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25474

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.00

AC:

AN:

85356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52570

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105528

Other (OTH)

AF:

0.0000167

AC:

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0086

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.31

M_CAP

Benign

0.019

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PhyloP100

-0.23

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

REVEL

Benign

0.082

Sift

Benign

0.082

Sift4G

Uncertain

0.021

Polyphen

0.0010

Vest4

0.25

MutPred

0.24

Gain of solvent accessibility (P = 0.006)

MVP

0.42

MPC

0.26

ClinPred

0.051

GERP RS

0.048

Varity_R

0.21

gMVP

0.41

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over