Genetic Variant NM_001002036.4:c.829A>C (chr2-96129869-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001002036.4(ASTL):c.829A>C(p.Lys277Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,594,978 control chromosomes in the GnomAD database, including 114,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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: 𝑓 0.36 ( 10521 hom., cov: 32)

Exomes 𝑓: 0.37 ( 104264 hom. )

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5303493E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASTL	NM_001002036.4 link	c.829A>C	p.Lys277Gln	missense_variant	Exon 8 of 9	ENST00000342380.3	NP_001002036.3	Q6HA08
ASTL	XM_011511205.3 link	c.844A>C	p.Lys282Gln	missense_variant	Exon 7 of 8		XP_011509507.1
ASTL	XM_011511207.3 link	c.790A>C	p.Lys264Gln	missense_variant	Exon 7 of 8		XP_011509509.1
ASTL	XM_011511208.3 link	c.734+195A>C		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>C	p.Lys277Gln	missense_variant	Exon 8 of 9	1	NM_001002036.4	ENSP00000343674.2		Q6HA08

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

54879

AN:

151938

Hom.:

10506

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.492

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.393

AC:

96751

AN:

246106

AF XY:

0.380

show subpopulations

Gnomad AFR exome

AF:

0.292

Gnomad AMR exome

AF:

0.509

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.628

Gnomad FIN exome

AF:

0.489

Gnomad NFE exome

AF:

0.367

Gnomad OTH exome

AF:

0.354

GnomAD4 exome

AF:

0.374

AC:

539292

AN:

1442922

Hom.:

104264

Cov.:

AF XY:

0.368

AC XY:

263155

AN XY:

714572

show subpopulations

African (AFR)

AF:

0.285

AC:

9425

AN:

33042

American (AMR)

AF:

0.499

AC:

21833

AN:

43752

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

6152

AN:

25600

East Asian (EAS)

AF:

0.575

AC:

22579

AN:

39274

South Asian (SAS)

AF:

0.264

AC:

22381

AN:

84886

European-Finnish (FIN)

AF:

0.488

AC:

25943

AN:

53130

Middle Eastern (MID)

AF:

0.185

AC:

865

AN:

4680

European-Non Finnish (NFE)

AF:

0.372

AC:

409262

AN:

1099224

Other (OTH)

AF:

0.351

AC:

20852

AN:

59334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

16232

32465

48697

64930

81162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13192

26384

39576

52768

65960

<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:

0.361

AC:

54944

AN:

152056

Hom.:

10521

Cov.:

AF XY:

0.366

AC XY:

27207

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.297

AC:

12301

AN:

41456

American (AMR)

AF:

0.402

AC:

6147

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

824

AN:

3470

East Asian (EAS)

AF:

0.612

AC:

3157

AN:

5162

South Asian (SAS)

AF:

0.270

AC:

1301

AN:

4820

European-Finnish (FIN)

AF:

0.492

AC:

5206

AN:

10584

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.365

AC:

24839

AN:

67960

Other (OTH)

AF:

0.319

AC:

673

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1786

3572

5357

7143

8929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.361

Hom.:

33972

Bravo

AF:

0.360

TwinsUK

AF:

0.365

AC:

1355

ALSPAC

AF:

0.371

AC:

1431

ESP6500AA

AF:

0.294

AC:

1297

ESP6500EA

AF:

0.362

AC:

3115

ExAC

AF:

0.383

AC:

46466

Asia WGS

AF:

0.383

AC:

1331

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.40

MetaRNN

Benign

0.00015

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.52

PhyloP100

0.87

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.079

Sift4G

Benign

0.32

Polyphen

0.026

Vest4

0.049

MPC

0.18

ClinPred

0.0070

GERP RS

-2.3

Varity_R

0.26

gMVP

0.57

Mutation Taster

=96/4

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over