Genetic Variant ANKRD53:p.Leu523Gln (chr2-70985275-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001115116.2(ANKRD53):c.1568T>A(p.Leu523Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,023,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00035 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANKRD53
NM_001115116.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0650

Publications

17 publications found

Variant links:

Genes affected

ANKRD53 (HGNC:25691): (ankyrin repeat domain 53) Involved in mitotic metaphase plate congression; regulation of microtubule cytoskeleton organization; and regulation of mitotic cytokinesis. Located in spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD53 links:

ENSG00000258881 (HGNC:):

ENSG00000258881 links:

TEX261 (HGNC:30712): (testis expressed 261) Predicted to enable COPII receptor activity. Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport. Predicted to act upstream of or within positive regulation of apoptotic process. Predicted to be located in cytoplasm. Predicted to be integral component of membrane. Predicted to be active in COPII-coated ER to Golgi transport vesicle. Predicted to be integral component of Golgi membrane and integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

TEX261 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1501486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD53	NM_001115116.2 link	c.1568T>A	p.Leu523Gln	missense_variant	Exon 6 of 6	ENST00000360589.4	NP_001108588.1	Q8N9V6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD53	ENST00000360589.4 link	c.1568T>A	p.Leu523Gln	missense_variant	Exon 6 of 6	2	NM_001115116.2	ENSP00000353796.3		Q8N9V6-1
ENSG00000258881	ENST00000606025.5 link	c.475+3640A>T		intron_variant	Intron 5 of 5	5		ENSP00000475641.1		U3KQ87

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

146336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000880

Gnomad SAS

AF:

0.000471

Gnomad FIN

AF:

0.000316

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.000487

GnomAD4 exome

AF:

0.000353

AC:

361

AN:

1023144

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

177

AN XY:

510546

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000513

AC:

AN:

23370

American (AMR)

AF:

0.0000318

AC:

AN:

31408

Ashkenazi Jewish (ASJ)

AF:

0.000160

AC:

AN:

18804

East Asian (EAS)

AF:

0.0000375

AC:

AN:

26680

South Asian (SAS)

AF:

0.000182

AC:

AN:

71568

European-Finnish (FIN)

AF:

0.0000268

AC:

AN:

37304

Middle Eastern (MID)

AF:

0.000475

AC:

AN:

4214

European-Non Finnish (NFE)

AF:

0.000406

AC:

312

AN:

767746

Other (OTH)

AF:

0.000380

AC:

AN:

42050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.233

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000164

AC:

AN:

146474

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

AN XY:

71356

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000248

AC:

AN:

40342

American (AMR)

AF:

0.000202

AC:

AN:

14826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.000882

AC:

AN:

4534

South Asian (SAS)

AF:

0.000470

AC:

AN:

4254

European-Finnish (FIN)

AF:

0.000316

AC:

AN:

9502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

66376

Other (OTH)

AF:

0.000482

AC:

AN:

2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.254

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

1154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0060

.;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

.;M

PhyloP100

-0.065

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.62

.;P

Vest4

0.16

MutPred

0.15

.;Gain of disorder (P = 0.0375);

MVP

0.74

MPC

0.62

ClinPred

0.44

GERP RS

0.84

Varity_R

0.15

gMVP

0.40

Mutation Taster

=100/0

polymorphism

(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