Genetic Variant ASTL:p.Lys277Glu (chr2-96129869-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001002036.4(ASTL):c.829A>G(p.Lys277Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ASTL
NM_001002036.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.866

Publications

33 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2648425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASTL	NM_001002036.4 link	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 9	ENST00000342380.3	NP_001002036.3	Q6HA08
ASTL	XM_011511205.3 link	c.844A>G	p.Lys282Glu	missense_variant	Exon 7 of 8		XP_011509507.1
ASTL	XM_011511207.3 link	c.790A>G	p.Lys264Glu	missense_variant	Exon 7 of 8		XP_011509509.1
ASTL	XM_011511208.3 link	c.734+195A>G		intron_variant	Intron 6 of 6		XP_011509510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASTL	ENST00000342380.3 link	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 9	1	NM_001002036.4	ENSP00000343674.2		Q6HA08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443696

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715008

African (AFR)

AF:

0.00

AC:

AN:

33066

American (AMR)

AF:

0.00

AC:

AN:

43818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25608

East Asian (EAS)

AF:

0.00

AC:

AN:

39294

South Asian (SAS)

AF:

0.00

AC:

AN:

84972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099742

Other (OTH)

AF:

0.00

AC:

AN:

59372

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.54

M_CAP

Benign

0.046

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.1

PhyloP100

0.87

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.3

REVEL

Benign

0.16

Sift

Benign

0.073

Sift4G

Benign

0.087

Polyphen

0.22

Vest4

0.14

MutPred

0.54

Loss of MoRF binding (P = 0.0028);

MVP

0.60

MPC

0.22

ClinPred

0.23

GERP RS

-2.3

Varity_R

0.29

gMVP

0.59

Mutation Taster

=96/4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over