dbSNP rs747588042: ANKRD9:p.Met283Thr (chr14-102507042-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152326.4(ANKRD9):c.848T>C(p.Met283Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000028 in 1,427,824 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: 0.0000028 ( 0 hom. )

Consequence

ANKRD9
NM_152326.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.00

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ANKRD9	NM_152326.4 link	c.848T>C	p.Met283Thr	missense_variant	Exon 4 of 4	ENST00000286918.9	NP_689539.1
ANKRD9	NM_001348651.2 link	c.848T>C	p.Met283Thr	missense_variant	Exon 4 of 4		NP_001335580.1
ANKRD9	NM_001348652.2 link	c.848T>C	p.Met283Thr	missense_variant	Exon 3 of 3		NP_001335581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKRD9	ENST00000286918.9 link	c.848T>C	p.Met283Thr	missense_variant	Exon 4 of 4	1	NM_152326.4	ENSP00000286918.4	Q96BM1
ANKRD9	ENST00000559651.1 link	c.848T>C	p.Met283Thr	missense_variant	Exon 2 of 2	1		ENSP00000454100.1	Q96BM1
ANKRD9	ENST00000560748.5 link	c.848T>C	p.Met283Thr	missense_variant	Exon 3 of 3	2		ENSP00000453650.1	Q96BM1
ANKRD9	ENST00000559404.5 link	c.*69T>C		downstream_gene_variant		2		ENSP00000453417.1	H0YM08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000526

AC:

AN:

190056

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1427824

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

709606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31786

American (AMR)

AF:

0.00

AC:

AN:

41916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.00

AC:

AN:

37856

South Asian (SAS)

AF:

0.00

AC:

AN:

82900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1103162

Other (OTH)

AF:

0.00

AC:

AN:

59392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000850

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.848T>C (p.M283T) alteration is located in exon 4 (coding exon 1) of the ANKRD9 gene. This alteration results from a T to C substitution at nucleotide position 848, causing the methionine (M) at amino acid position 283 to be replaced by a threonine (T). 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

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.40

.;.;T

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.4

M;M;M

PhyloP100

6.0

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.96

D;D;D

Vest4

0.56

MutPred

0.81

Loss of helix (P = 0.0072);Loss of helix (P = 0.0072);Loss of helix (P = 0.0072);

MVP

0.98

MPC

2.4

ClinPred

0.93

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.57

gMVP

0.63

Mutation Taster

=70/30

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over