20-56386485-A-G

Variant names:

• chr20-56386485-A-G
• rs2273535
• NM_198437.3:c.91T>C
• AURKA p.Phe31Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_198437.3(AURKA):c.91T>C (p.Phe31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F31I: Benign (ClinVar VariationId 6642, 2 stars)

• Frequency: Genomes: not found (cov: 33)
• Consequence: AURKA NM_198437.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.555
• Publications: 216 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_198437.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AURKA NM_198437.3	MANE Select	c.91T>C p.Phe31Leu	missense	Exon 3 of 9	Prot: NP_940839.1 UniProt:
	AURKA NM_001424418.1		c.193T>C p.Phe65Leu	missense	Exon 5 of 11	Prot: NP_001411347.1
	AURKA NM_001424419.1		c.193T>C p.Phe65Leu	missense	Exon 5 of 11	Prot: NP_001411348.1

AURKA NM_198437.3

MANE Select

HGVSc / HGVSpc.91T>Cp.Phe31Leu

Exon rankExon 3 of 9

missense

Prot: NP_940839.1UniProt: O14965

AURKA NM_001424418.1

HGVSc / HGVSpc.193T>Cp.Phe65Leu

Exon rankExon 5 of 11

missense

Prot: NP_001411347.1

AURKA NM_001424419.1

HGVSc / HGVSpc.193T>Cp.Phe65Leu

Exon rankExon 5 of 11

missense

Prot: NP_001411348.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AURKA ENST00000395915.8	TSL:1MANE Select	c.91T>C p.Phe31Leu	missense	Exon 3 of 9	Prot: ENSP00000379251.3 UniProt:
	AURKA ENST00000312783.10	TSL:1	c.91T>C p.Phe31Leu	missense	Exon 4 of 10	Prot: ENSP00000321591.6 UniProt:
	AURKA ENST00000347343.6	TSL:1	c.91T>C p.Phe31Leu	missense	Exon 3 of 9	Prot: ENSP00000216911.2 UniProt:

AURKA ENST00000395915.8

TSL:1MANE Select

HGVSc / HGVSpc.91T>Cp.Phe31Leu

Exon rankExon 3 of 9

missense

Prot: ENSP00000379251.3UniProt: O14965

AURKA ENST00000312783.10

TSL:1

HGVSc / HGVSpc.91T>Cp.Phe31Leu

Exon rankExon 4 of 10

missense

Prot: ENSP00000321591.6UniProt: O14965

AURKA ENST00000347343.6

TSL:1

HGVSc / HGVSpc.91T>Cp.Phe31Leu

Exon rankExon 3 of 9

missense

Prot: ENSP00000216911.2UniProt: O14965

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:41
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	12
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.34
DANN	Benign	0.29
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.079	N
FuncVEP CTI	Benign	0.00077
GPN-Star LLR	N/A	-2.2
GPN-Star score	N/A	2.2
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	100/0	polymorphism
PhyloP100	Benign	-0.56
popEVE	Benign	-3.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.066
Sift	Benign	0.80	T
Sift4G	Benign	0.65	T
VESM-3B	Benign	-1.1

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2273535;

hg19: chr20-54961541;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar