Variant 2-96124235-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001002036.4(ASTL):c.911C>T(p.Pro304Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,515,658 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

ASTL
NM_001002036.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0590

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027956426).

BP6

Variant 2-96124235-G-A is Benign according to our data. Variant chr2-96124235-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2457080.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ASTL	NM_001002036.4 linkuse as main transcript	c.911C>T	p.Pro304Leu	missense_variant	9/9	ENST00000342380.3	NP_001002036.3
ASTL	XM_011511205.3 linkuse as main transcript	c.926C>T	p.Pro309Leu	missense_variant	8/8		XP_011509507.1
ASTL	XM_011511207.3 linkuse as main transcript	c.872C>T	p.Pro291Leu	missense_variant	8/8		XP_011509509.1
ASTL	XM_011511208.3 linkuse as main transcript	c.*12C>T		3_prime_UTR_variant	7/7		XP_011509510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASTL	ENST00000342380.3 linkuse as main transcript	c.911C>T	p.Pro304Leu	missense_variant	9/9	1	NM_001002036.4	ENSP00000343674	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000414

AC:

AN:

169232

Hom.:

AF XY:

0.0000331

AC XY:

AN XY:

90648

show subpopulations

Gnomad AFR exome

AF:

0.0000736

Gnomad AMR exome

AF:

0.000194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000702

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000330

AC:

AN:

1363346

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

667622

show subpopulations

Gnomad4 AFR exome

AF:

0.0000662

Gnomad4 AMR exome

AF:

0.0000691

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000571

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000300

Gnomad4 OTH exome

AF:

0.0000892

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000344

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.0076

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.57

M_CAP

Benign

0.015

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.75

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.7

REVEL

Benign

0.042

Sift

Benign

0.090

Sift4G

Benign

0.12

Polyphen

0.027

Vest4

0.085

MutPred

0.24

Loss of glycosylation at P304 (P = 0.0167);

MVP

0.36

MPC

0.14

ClinPred

0.016

GERP RS

1.1

Varity_R

0.031

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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