Variant chr2-96129860-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001002036.4(ASTL):c.838G>A(p.Gly280Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,592,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

ASTL
NM_001002036.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.158

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02204284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ASTL	NM_001002036.4 linkuse as main transcript	c.838G>A	p.Gly280Ser	missense_variant	8/9	ENST00000342380.3	NP_001002036.3
ASTL	XM_011511205.3 linkuse as main transcript	c.853G>A	p.Gly285Ser	missense_variant	7/8		XP_011509507.1
ASTL	XM_011511207.3 linkuse as main transcript	c.799G>A	p.Gly267Ser	missense_variant	7/8		XP_011509509.1
ASTL	XM_011511208.3 linkuse as main transcript	c.734+204G>A		intron_variant			XP_011509510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASTL	ENST00000342380.3 linkuse as main transcript	c.838G>A	p.Gly280Ser	missense_variant	8/9	1	NM_001002036.4	ENSP00000343674	P1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.000131

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:

0.000382

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000325

AC:

AN:

243214

Hom.:

AF XY:

0.000290

AC XY:

AN XY:

131218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000481

Gnomad OTH exome

AF:

0.000676

GnomAD4 exome

AF:

0.000489

AC:

704

AN:

1440016

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

326

AN XY:

712908

show subpopulations

Gnomad4 AFR exome

AF:

0.0000607

Gnomad4 AMR exome

AF:

0.000530

Gnomad4 ASJ exome

AF:

0.0000394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.000581

Gnomad4 OTH exome

AF:

0.000591

GnomAD4 genome

AF:

0.000250

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000438

Hom.:

Bravo

AF:

0.000329

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.838G>A (p.G280S) alteration is located in exon 8 (coding exon 8) of the ASTL gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glycine (G) at amino acid position 280 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.032

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.56

M_CAP

Benign

0.014

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.42

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.48

REVEL

Benign

0.031

Sift

Benign

0.23

Sift4G

Benign

0.68

Polyphen

0.022

Vest4

0.057

MVP

0.45

MPC

0.15

ClinPred

0.027

GERP RS

2.3

Varity_R

0.035

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over