20-56386407-T-C

Variant names:

• chr20-56386407-T-C
• rs1047972
• NM_198437.3:c.169A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_198437.3(AURKA):​c.169A>G​(p.Ile57Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,986 control chromosomes in the GnomAD database, including 575,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I57F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.84 (54283 hom., cov: 31)
  • Exomes 𝑓: 0.84 (520862 hom.)
• Consequence: AURKA NM_198437.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.556
• Publications: 124 publications found

Genes affected

AURKA (HGNC:11393): (aurora kinase A) The protein encoded by this gene is a cell cycle-regulated kinase that appears to be involved in microtubule formation and/or stabilization at the spindle pole during chromosome segregation. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. This gene may play a role in tumor development and progression. A processed pseudogene of this gene has been found on chromosome 1, and an unprocessed pseudogene has been found on chromosome 10. Multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

AURKA Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0621073E-7).
• BP6: Variant 20-56386407-T-C is Benign according to our data. Variant chr20-56386407-T-C is described in ClinVar as Benign. ClinVar VariationId is 3059051.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198437.3. 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
	AURKA	NM_198437.3	MANE Select	c.169A>G	p.Ile57Val	missense	Exon 3 of 9	NP_940839.1	O14965
	AURKA	NM_001424418.1		c.271A>G	p.Ile91Val	missense	Exon 5 of 11	NP_001411347.1
	AURKA	NM_001424419.1		c.271A>G	p.Ile91Val	missense	Exon 5 of 11	NP_001411348.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AURKA	ENST00000395915.8	TSL:1 MANE Select	c.169A>G	p.Ile57Val	missense	Exon 3 of 9	ENSP00000379251.3	O14965
	AURKA	ENST00000312783.10	TSL:1	c.169A>G	p.Ile57Val	missense	Exon 4 of 10	ENSP00000321591.6	O14965
	AURKA	ENST00000347343.6	TSL:1	c.169A>G	p.Ile57Val	missense	Exon 3 of 9	ENSP00000216911.2	O14965

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128366 AN: 152010 Hom.: 54229 Cov.: 31

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.892

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.860

GnomAD2 exomes AF: 0.851 AC: 213970 AN: 251486 AF XY: 0.848

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.853

Gnomad EAS exome AF: 0.878

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.842

GnomAD4 exome AF: 0.844 AC: 1233537 AN: 1461858 Hom.: 520862 Cov.: 88 AF XY: 0.844 AC XY: 613833 AN XY: 727230

African (AFR) AF: 0.834 AC: 27934 AN: 33480

American (AMR) AF: 0.912 AC: 40766 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 22435 AN: 26136

East Asian (EAS) AF: 0.871 AC: 34571 AN: 39700

South Asian (SAS) AF: 0.858 AC: 73996 AN: 86258

European-Finnish (FIN) AF: 0.810 AC: 43274 AN: 53420

Middle Eastern (MID) AF: 0.835 AC: 4819 AN: 5768

European-Non Finnish (NFE) AF: 0.840 AC: 934582 AN: 1111978

Other (OTH) AF: 0.847 AC: 51160 AN: 60396

GnomAD4 genome AF: 0.845 AC: 128476 AN: 152128 Hom.: 54283 Cov.: 31 AF XY: 0.843 AC XY: 62696 AN XY: 74386

African (AFR) AF: 0.838 AC: 34768 AN: 41488

American (AMR) AF: 0.887 AC: 13570 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 3004 AN: 3472

East Asian (EAS) AF: 0.880 AC: 4548 AN: 5166

South Asian (SAS) AF: 0.855 AC: 4123 AN: 4820

European-Finnish (FIN) AF: 0.810 AC: 8562 AN: 10568

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 57020 AN: 68004

Other (OTH) AF: 0.856 AC: 1809 AN: 2114

Alfa AF: 0.840 Hom.: 263613

Bravo AF: 0.850

TwinsUK AF: 0.841 AC: 3119

ALSPAC AF: 0.847 AC: 3265

ESP6500AA AF: 0.838 AC: 3693

ESP6500EA AF: 0.838 AC: 7203

ExAC AF: 0.848 AC: 102977

Asia WGS AF: 0.872 AC: 3034 AN: 3478

EpiCase AF: 0.829

EpiControl AF: 0.826

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	AURKA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.032
DANN	Benign	0.21
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.016	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.56
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.010
ClinPred		0.00020	T
GERP RS		2.0
gMVP		0.092
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1047972; hg19: chr20-54961463; COSMIC: COSV100452806;