Genetic Variant NM_152363.6:c.91G>A (chr19-17282085-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_152363.6(ANKLE1):c.91G>A(p.Ala31Thr) variant causes a missense change. The variant allele was found at a frequency of 0.5 in 1,539,996 control chromosomes in the GnomAD database, including 193,706 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.47 ( 17095 hom., cov: 34)

Exomes 𝑓: 0.50 ( 176611 hom. )

Consequence

ANKLE1
NM_152363.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.49

Publications

90 publications found

Variant links:

Genes affected

ANKLE1 (HGNC:26812): (ankyrin repeat and LEM domain containing 1) Enables endonuclease activity. Involved in positive regulation of response to DNA damage stimulus and protein export from nucleus. Located in cytosol and nucleoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ANKLE1 links:

ENSG00000269307 (HGNC:):

ENSG00000269307 links:

USHBP1 (HGNC:24058): (USH1 protein network component harmonin binding protein 1) Enables PDZ domain binding activity. [provided by Alliance of Genome Resources, Apr 2022]

USHBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.9503317E-4).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKLE1	NM_152363.6 link	c.91G>A	p.Ala31Thr	missense_variant	Exon 2 of 9	ENST00000404085.7	NP_689576.6	Q8NAG6-2A0A499FJM0B4E124

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKLE1	ENST00000404085.7 link	c.91G>A	p.Ala31Thr	missense_variant	Exon 2 of 9	2	NM_152363.6	ENSP00000384008.3	Q8NAG6-2
ENSG00000269307	ENST00000596542.1 link	n.*424G>A		non_coding_transcript_exon_variant	Exon 8 of 10	2		ENSP00000469159.2	M0QXG9
ENSG00000269307	ENST00000596542.1 link	n.*424G>A		3_prime_UTR_variant	Exon 8 of 10	2		ENSP00000469159.2	M0QXG9

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71562

AN:

151974

Hom.:

17080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.424

Gnomad ASJ

AF:

0.509

Gnomad EAS

AF:

0.319

Gnomad SAS

AF:

0.477

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.515

Gnomad OTH

AF:

0.468

GnomAD2 exomes

AF:

0.466

AC:

63343

AN:

135892

AF XY:

0.470

show subpopulations

Gnomad AFR exome

AF:

0.402

Gnomad AMR exome

AF:

0.397

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.313

Gnomad FIN exome

AF:

0.554

Gnomad NFE exome

AF:

0.514

Gnomad OTH exome

AF:

0.476

GnomAD4 exome

AF:

0.503

AC:

697696

AN:

1387904

Hom.:

176611

Cov.:

AF XY:

0.502

AC XY:

343540

AN XY:

684930

show subpopulations

African (AFR)

AF:

0.398

AC:

12569

AN:

31564

American (AMR)

AF:

0.396

AC:

14139

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

12658

AN:

25156

East Asian (EAS)

AF:

0.320

AC:

11438

AN:

35714

South Asian (SAS)

AF:

0.472

AC:

37358

AN:

79206

European-Finnish (FIN)

AF:

0.558

AC:

21545

AN:

38596

Middle Eastern (MID)

AF:

0.503

AC:

2781

AN:

5532

European-Non Finnish (NFE)

AF:

0.516

AC:

556338

AN:

1078598

Other (OTH)

AF:

0.499

AC:

28870

AN:

57858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

24847

49694

74541

99388

124235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16196

32392

48588

64784

80980

<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:

0.471

AC:

71626

AN:

152092

Hom.:

17095

Cov.:

AF XY:

0.471

AC XY:

35052

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.405

AC:

16820

AN:

41492

American (AMR)

AF:

0.423

AC:

6465

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.509

AC:

1765

AN:

3468

East Asian (EAS)

AF:

0.318

AC:

1641

AN:

5154

South Asian (SAS)

AF:

0.478

AC:

2310

AN:

4834

European-Finnish (FIN)

AF:

0.569

AC:

6031

AN:

10594

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.515

AC:

35001

AN:

67956

Other (OTH)

AF:

0.473

AC:

998

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1967

3934

5900

7867

9834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.499

Hom.:

34507

Bravo

AF:

0.457

TwinsUK

AF:

0.499

AC:

1850

ALSPAC

AF:

0.507

AC:

1954

ESP6500AA

AF:

0.366

AC:

1171

ESP6500EA

AF:

0.474

AC:

2712

ExAC

AF:

0.397

AC:

9415

Asia WGS

AF:

0.422

AC:

1466

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.64

T;.

MetaRNN

Benign

0.00060

T;T

MetaSVM

Benign

-0.91

PhyloP100

5.5

PrimateAI

Pathogenic

0.87

REVEL

Uncertain

0.36

Sift4G

Uncertain

0.028

D;D

Vest4

0.096

MPC

0.70

ClinPred

0.032

GERP RS

1.6

PromoterAI

0.00040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.57

Mutation Taster

=97/3

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