Variant 14-102507120-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152326.4(ANKRD9):c.770G>A(p.Arg257His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000917 in 1,492,982 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 2 hom. )

Consequence

ANKRD9
NM_152326.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0790

Variant links:

Genes affected

ANKRD9 (HGNC:20096): (ankyrin repeat domain 9) Enables ubiquitin ligase-substrate adaptor activity. Involved in cellular copper ion homeostasis; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Located in cytoplasmic vesicle and cytosol. Part of Cul5-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD9 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014211088).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ANKRD9	NM_152326.4 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	4/4	ENST00000286918.9	NP_689539.1
ANKRD9	NM_001348651.2 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	4/4		NP_001335580.1
ANKRD9	NM_001348652.2 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	3/3		NP_001335581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ANKRD9	ENST00000286918.9 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	4/4	1	NM_152326.4	ENSP00000286918	P1
ANKRD9	ENST00000559651.1 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	2/2	1		ENSP00000454100	P1
ANKRD9	ENST00000560748.5 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	3/3	2		ENSP00000453650	P1
ANKRD9	ENST00000559404.5 linkuse as main transcript	c.770G>A	p.Arg257His	missense_variant	3/3	2		ENSP00000453417

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000637

AC:

AN:

92684

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

52544

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000513

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:

0.00129

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.000956

AC:

1282

AN:

1340968

Hom.:

Cov.:

AF XY:

0.000942

AC XY:

622

AN XY:

660486

show subpopulations

Gnomad4 AFR exome

AF:

0.000146

Gnomad4 AMR exome

AF:

0.000401

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000108

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000715

GnomAD4 genome

AF:

0.000572

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000421

Hom.:

Bravo

AF:

0.000627

ExAC

AF:

0.000318

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.770G>A (p.R257H) alteration is located in exon 4 (coding exon 1) of the ANKRD9 gene. This alteration results from a G to A substitution at nucleotide position 770, causing the arginine (R) at amino acid position 257 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T;T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.78

.;.;T;T

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.5

L;L;L;.

MutationTaster

Benign

0.96

N;N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.68

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.56

T;T;T;T

Sift4G

Benign

0.55

T;T;T;.

Polyphen

0.088

B;B;B;.

Vest4

0.093

MVP

0.90

MPC

1.5

ClinPred

0.014

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.058

gMVP

0.29

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