Genetic Variant ANKRD46:p.Asp123Asn (chr8-100527948-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001270377.2(ANKRD46):c.367G>A(p.Asp123Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,591,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D123E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANKRD46
NM_001270377.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81

Variant links:

Genes affected

ANKRD46 (HGNC:27229): (ankyrin repeat domain 46) This gene encodes a protein containing multiple ankyrin repeats. Ankyrin domains function in protein-protein interactions in a variety of cellular processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ANKRD46 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38293988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD46	NM_001270377.2 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 4 of 5	ENST00000335659.7	NP_001257306.1	Q86W74-2A0A024R9E1B3KT99
ANKRD46	NM_001270379.2 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 4 of 6		NP_001257308.1	Q86W74-1A0A024R9G2
ANKRD46	NM_001270378.2 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 4 of 5		NP_001257307.1	Q86W74-2A0A024R9E1
ANKRD46	NM_198401.4 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 5 of 6		NP_940683.1	Q86W74-2A0A024R9E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD46	ENST00000335659.7 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 4 of 5	1	NM_001270377.2	ENSP00000335287.3		Q86W74-2

Frequencies

GnomAD3 genomes

AF:

0.0000282

AC:

AN:

141860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251296

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000282

AC:

AN:

141860

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

68136

show subpopulations

Gnomad4 AFR

AF:

0.000105

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.367G>A (p.D123N) alteration is located in exon 5 (coding exon 2) of the ANKRD46 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the aspartic acid (D) at amino acid position 123 to be replaced by an asparagine (N). 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

0.23

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0052

T;.;.;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;.;.;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.55

N;N;N;N;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.024

D;T;T;T;T

Sift4G

Uncertain

0.048

D;T;T;T;T

Polyphen

0.46

P;D;D;D;.

Vest4

0.53

MutPred

0.53

Gain of MoRF binding (P = 0.0394);Gain of MoRF binding (P = 0.0394);Gain of MoRF binding (P = 0.0394);Gain of MoRF binding (P = 0.0394);Gain of MoRF binding (P = 0.0394);

MVP

0.43

MPC

1.3

ClinPred

0.67

GERP RS

5.5

Varity_R

0.27

gMVP

0.76

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