14-102507346-C-G

Variant names:

• chr14-102507346-C-G
• rs1396147502
• NM_152326.4:c.544G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152326.4(ANKRD9):​c.544G>C​(p.Gly182Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000378 in 1,323,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G182S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ANKRD9 NM_152326.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.11
• Publications: 0 publications found

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]

ACMG classification

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, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152326.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD9	NM_152326.4	MANE Select	c.544G>C	p.Gly182Arg	missense	Exon 4 of 4	NP_689539.1	Q96BM1
	ANKRD9	NM_001348651.2		c.544G>C	p.Gly182Arg	missense	Exon 4 of 4	NP_001335580.1	Q96BM1
	ANKRD9	NM_001348652.2		c.544G>C	p.Gly182Arg	missense	Exon 3 of 3	NP_001335581.1	Q96BM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD9	ENST00000286918.9	TSL:1 MANE Select	c.544G>C	p.Gly182Arg	missense	Exon 4 of 4	ENSP00000286918.4	Q96BM1
	ANKRD9	ENST00000559651.1	TSL:1	c.544G>C	p.Gly182Arg	missense	Exon 2 of 2	ENSP00000454100.1	Q96BM1
	ANKRD9	ENST00000560748.5	TSL:2	c.544G>C	p.Gly182Arg	missense	Exon 3 of 3	ENSP00000453650.1	Q96BM1

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148648 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 36798 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000340 AC: 4 AN: 1174804 Hom.: 0 Cov.: 30 AF XY: 0.00000520 AC XY: 3 AN XY: 577380

African (AFR) AF: 0.00 AC: 0 AN: 21502

American (AMR) AF: 0.00 AC: 0 AN: 12134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16122

East Asian (EAS) AF: 0.000153 AC: 3 AN: 19632

South Asian (SAS) AF: 0.00 AC: 0 AN: 61204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3188

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 966738

Other (OTH) AF: 0.00 AC: 0 AN: 45438

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148756 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72558

African (AFR) AF: 0.00 AC: 0 AN: 41238

American (AMR) AF: 0.00 AC: 0 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66634

Other (OTH) AF: 0.00 AC: 0 AN: 2072

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.1
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.82		Gain of phosphorylation at S184 (P = 0.0918)
MVP		0.83
MPC		2.7
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.78
gMVP		0.74
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs1396147502; hg19: chr14-102973683;