chr14-102507250-C-T

Variant names:

• chr14-102507250-C-T
• rs2139814184
• NM_152326.4:c.640G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152326.4(ANKRD9):​c.640G>A​(p.Ala214Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000037 in 1,080,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: ANKRD9 NM_152326.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.102
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15961117).

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.640G>A	p.Ala214Thr	missense	Exon 4 of 4	NP_689539.1	Q96BM1
	ANKRD9	NM_001348651.2		c.640G>A	p.Ala214Thr	missense	Exon 4 of 4	NP_001335580.1	Q96BM1
	ANKRD9	NM_001348652.2		c.640G>A	p.Ala214Thr	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.640G>A	p.Ala214Thr	missense	Exon 4 of 4	ENSP00000286918.4	Q96BM1
	ANKRD9	ENST00000559651.1	TSL:1	c.640G>A	p.Ala214Thr	missense	Exon 2 of 2	ENSP00000454100.1	Q96BM1
	ANKRD9	ENST00000560748.5	TSL:2	c.640G>A	p.Ala214Thr	missense	Exon 3 of 3	ENSP00000453650.1	Q96BM1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000370 AC: 4 AN: 1080472 Hom.: 0 Cov.: 30 AF XY: 0.00000579 AC XY: 3 AN XY: 517858

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20898

American (AMR) AF: 0.00 AC: 0 AN: 6822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12354

East Asian (EAS) AF: 0.00 AC: 0 AN: 21022

South Asian (SAS) AF: 0.00 AC: 0 AN: 32964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2806

European-Non Finnish (NFE) AF: 0.00000327 AC: 3 AN: 918306

Other (OTH) AF: 0.0000239 AC: 1 AN: 41892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0249301), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	2.8
DANN	Benign	0.93
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.10
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.17
Sift	Benign	0.035	D
Sift4G	Benign	0.43	T
Polyphen		0.021	B
Vest4		0.049
MutPred		0.21		Gain of glycosylation at A214 (P = 0.0044)
MVP		0.80
MPC		1.2
ClinPred		0.038	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.034
gMVP		0.17
Mutation Taster		=95/5	polymorphism

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: rs2139814184; hg19: chr14-102973587;