14-102507250-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/21 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD9	NM_152326.4	c.640G>A	p.Ala214Thr	missense_variant	Exon 4 of 4	ENST00000286918.9	NP_689539.1
ANKRD9	NM_001348651.2	c.640G>A	p.Ala214Thr	missense_variant	Exon 4 of 4		NP_001335580.1
ANKRD9	NM_001348652.2	c.640G>A	p.Ala214Thr	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	c.640G>A	p.Ala214Thr	missense_variant	Exon 4 of 4	1	NM_152326.4	ENSP00000286918.4
ANKRD9	ENST00000559651.1	c.640G>A	p.Ala214Thr	missense_variant	Exon 2 of 2	1		ENSP00000454100.1
ANKRD9	ENST00000560748.5	c.640G>A	p.Ala214Thr	missense_variant	Exon 3 of 3	2		ENSP00000453650.1
ANKRD9	ENST00000559404.5	c.640G>A	p.Ala214Thr	missense_variant	Exon 3 of 3	2		ENSP00000453417.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000327

Gnomad4 OTH exome AF: 0.0000239

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640G>A (p.A214T) 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 640, causing the alanine (A) at amino acid position 214 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	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;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.40	.;.;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L;L;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.47	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.035	D;D;D;D
Sift4G	Benign	0.43	T;T;T;.
Polyphen		0.021	B;B;B;.
Vest4		0.049
MutPred		0.21		Gain of glycosylation at A214 (P = 0.0044);Gain of glycosylation at A214 (P = 0.0044);Gain of glycosylation at A214 (P = 0.0044);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-102973587;