Genetic Variant ASTL:p.Pro304Pro (chr2-96124234-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001002036.4(ASTL):c.912G>A(p.Pro304Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,514,630 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0048 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 40 hom. )

Consequence

ASTL
NM_001002036.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.68

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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-96124234-C-T is Benign according to our data. Variant chr2-96124234-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2651138.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.68 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASTL	NM_001002036.4 link	c.912G>A	p.Pro304Pro	synonymous_variant	Exon 9 of 9	ENST00000342380.3	NP_001002036.3	Q6HA08
ASTL	XM_011511205.3 link	c.927G>A	p.Pro309Pro	synonymous_variant	Exon 8 of 8		XP_011509507.1
ASTL	XM_011511207.3 link	c.873G>A	p.Pro291Pro	synonymous_variant	Exon 8 of 8		XP_011509509.1
ASTL	XM_011511208.3 link	c.*13G>A		3_prime_UTR_variant	Exon 7 of 7		XP_011509510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASTL	ENST00000342380.3 link	c.912G>A	p.Pro304Pro	synonymous_variant	Exon 9 of 9	1	NM_001002036.4	ENSP00000343674.2		Q6HA08

Frequencies

GnomAD3 genomes

AF:

0.00485

AC:

737

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00656

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00535

AC:

904

AN:

168838

AF XY:

0.00554

show subpopulations

Gnomad AFR exome

AF:

0.000961

Gnomad AMR exome

AF:

0.00890

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00122

Gnomad NFE exome

AF:

0.00718

Gnomad OTH exome

AF:

0.00836

GnomAD4 exome

AF:

0.00585

AC:

7970

AN:

1362438

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

3824

AN XY:

667084

show subpopulations

Gnomad4 AFR exome

AF:

0.000894

AC:

AN:

30194

Gnomad4 AMR exome

AF:

0.00949

AC:

274

AN:

28886

Gnomad4 ASJ exome

AF:

0.00943

AC:

187

AN:

19822

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

38794

Gnomad4 SAS exome

AF:

0.00167

AC:

117

AN:

69968

Gnomad4 FIN exome

AF:

0.00166

AC:

AN:

48674

Gnomad4 NFE exome

AF:

0.00652

AC:

6948

AN:

1065030

Gnomad4 Remaining exome

AF:

0.00564

AC:

316

AN:

55994

Heterozygous variant carriers

432

863

1295

1726

2158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00484

AC:

736

AN:

152192

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

375

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00111

AC:

0.00110785

AN:

0.00110785

Gnomad4 AMR

AF:

0.0107

AC:

0.0106522

AN:

0.0106522

Gnomad4 ASJ

AF:

0.00923

AC:

0.00922722

AN:

0.00922722

Gnomad4 EAS

AF:

0.000193

AC:

0.000193498

AN:

0.000193498

Gnomad4 SAS

AF:

0.00166

AC:

0.00165975

AN:

0.00165975

Gnomad4 FIN

AF:

0.00170

AC:

0.00169683

AN:

0.00169683

Gnomad4 NFE

AF:

0.00656

AC:

0.00655998

AN:

0.00655998

Gnomad4 OTH

AF:

0.00568

AC:

0.00568182

AN:

0.00568182

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.00544

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASTL: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.71

DANN

Benign

0.60

Mutation Taster

=100/0

polymorphism

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