Genetic Variant ANKRD33:p.Lys55Ile (chr12-51888586-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_182608.4(ANKRD33):c.164A>T(p.Lys55Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,403,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ANKRD33
NM_182608.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.511

Publications

0 publications found

Variant links:

Genes affected

ANKRD33 (HGNC:13788): (ankyrin repeat domain 33) Predicted to be involved in negative regulation of transcription by RNA polymerase II and negative regulation of transcription regulatory region DNA binding activity. Predicted to act upstream of or within skeletal muscle cell differentiation. Predicted to be located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD33 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05199167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD33	NM_182608.4 link	c.164A>T	p.Lys55Ile	missense_variant	Exon 2 of 5	ENST00000301190.11	NP_872414.3	Q7Z3H0-2Q0VAA8Q5K617

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD33	ENST00000301190.11 link	c.164A>T	p.Lys55Ile	missense_variant	Exon 2 of 5	2	NM_182608.4	ENSP00000301190.6		Q7Z3H0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000494

AC:

AN:

202404

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000595

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1403096

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

692724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31224

American (AMR)

AF:

0.00

AC:

AN:

34418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21772

East Asian (EAS)

AF:

0.0000764

AC:

AN:

39246

South Asian (SAS)

AF:

0.00

AC:

AN:

76684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085386

Other (OTH)

AF:

0.00

AC:

AN:

57674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.164A>T (p.K55I) alteration is located in exon 2 (coding exon 2) of the ANKRD33 gene. This alteration results from a A to T substitution at nucleotide position 164, causing the lysine (K) at amino acid position 55 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.88

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.27

M_CAP

Benign

0.0022

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.0

PhyloP100

0.51

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.56

REVEL

Benign

0.043

Sift

Benign

0.047

Sift4G

Benign

0.061

Vest4

0.26

MutPred

0.38

Loss of solvent accessibility (P = 7e-04);

MVP

0.055

MPC

0.22

ClinPred

0.30

GERP RS

-0.11

PromoterAI

0.019

Neutral

(source)

Varity_R

0.15

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(source)

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

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12-51888586-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over