Genetic Variant NM_021913.5:c.130A>G (chr19-41220680-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021913.5(AXL):c.130A>G(p.Ile44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,609,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

AXL
NM_021913.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0350

Publications

0 publications found

Variant links:

Genes affected

AXL (HGNC:905): (AXL receptor tyrosine kinase) The protein encoded by this gene is a member of the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase subfamily. The encoded protein possesses an extracellular domain which is composed of two immunoglobulin-like motifs at the N-terminal, followed by two fibronectin type-III motifs. It transduces signals from the extracellular matrix into the cytoplasm by binding to the vitamin K-dependent protein growth arrest-specific 6 (Gas6). This gene may be involved in several cellular functions including growth, migration, aggregation and anti-inflammation in multiple cell types. The encoded protein acts as a host cell receptor for multiple viruses, including Marburg, Ebola and Lassa viruses and is a candidate receptor for the SARS-CoV2 virus. [provided by RefSeq, Sep 2021]

AXL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057537258).

BS2

High AC in GnomAdExome4 at 158 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021913.5. 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
	AXL	NM_021913.5	MANE Select	c.130A>G	p.Ile44Val	missense	Exon 2 of 20	NP_068713.2
	AXL	NM_001699.6		c.130A>G	p.Ile44Val	missense	Exon 2 of 19	NP_001690.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AXL	ENST00000301178.9	TSL:1 MANE Select	c.130A>G	p.Ile44Val	missense	Exon 2 of 20	ENSP00000301178.3	P30530-1
AXL	ENST00000359092.7	TSL:1	c.130A>G	p.Ile44Val	missense	Exon 2 of 19	ENSP00000351995.2	P30530-2
AXL	ENST00000599659.5	TSL:1	n.144A>G		non_coding_transcript_exon	Exon 2 of 12

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000250

AC:

AN:

239654

AF XY:

0.0000154

show subpopulations

Gnomad AFR exome

AF:

0.0000652

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:

0.0000466

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1456878

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

724318

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

43876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39446

South Asian (SAS)

AF:

0.00

AC:

AN:

85318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000135

AC:

150

AN:

1109802

Other (OTH)

AF:

0.000116

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.7

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.16

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.63

M_CAP

Benign

0.012

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.33

PhyloP100

-0.035

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.36

REVEL

Benign

0.047

Sift

Benign

0.34

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.27

MutPred

0.41

Gain of disorder (P = 0.0796)

MVP

0.31

MPC

0.21

ClinPred

0.017

GERP RS

-0.12

Varity_R

0.037

gMVP

0.097

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over