Genetic Variant ANKRD9:p.Gly159Ser (chr14-102507415-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152326.4(ANKRD9):c.475G>A(p.Gly159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

ANKRD9
NM_152326.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.29

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ANKRD9	NM_152326.4 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 4 of 4	ENST00000286918.9	NP_689539.1
ANKRD9	NM_001348651.2 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 4 of 4		NP_001335580.1
ANKRD9	NM_001348652.2 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 3 of 3		NP_001335581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD9	ENST00000286918.9 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 4 of 4	1	NM_152326.4	ENSP00000286918.4		Q96BM1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.22e-7

AC:

AN:

1217138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

598768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000618

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.475G>A (p.G159S) 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 475, causing the glycine (G) at amino acid position 159 to be replaced by a serine (S). 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

0.17

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

.;.;T;T

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.5

M;M;M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Uncertain

0.43

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.17

T;T;T;.

Polyphen

1.0

D;D;D;.

Vest4

0.26

MutPred

0.64

Gain of glycosylation at G159 (P = 0.0093);Gain of glycosylation at G159 (P = 0.0093);Gain of glycosylation at G159 (P = 0.0093);Gain of glycosylation at G159 (P = 0.0093);

MVP

0.87

MPC

2.5

ClinPred

0.99

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.69

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