19-41219397-C-T

Position:

chr19-41219397-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000301178.9(AXL):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,597,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

AXL
ENST00000301178.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.940

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:

AXL (HGNC:):

AXL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037536055).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXL	NM_021913.5 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/20	ENST00000301178.9	NP_068713.2	P30530-1
AXL	NM_001699.6 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/19		NP_001690.2	P30530-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AXL	ENST00000301178.9 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/20	1	NM_021913.5	ENSP00000301178.3	P30530-1
AXL	ENST00000359092.7 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/19	1		ENSP00000351995.2	P30530-2
AXL	ENST00000599659.5 linkuse as main transcript	n.19C>T		non_coding_transcript_exon_variant	1/12	1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000552

AC:

AN:

217510

Hom.:

AF XY:

0.0000254

AC XY:

AN XY:

118156

show subpopulations

Gnomad AFR exome

AF:

0.000468

Gnomad AMR exome

AF:

0.0000629

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000598

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000209

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000325

AC:

AN:

1445018

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

717226

show subpopulations

Gnomad4 AFR exome

AF:

0.000271

Gnomad4 AMR exome

AF:

0.0000707

Gnomad4 ASJ exome

AF:

0.0000389

Gnomad4 EAS exome

AF:

0.0000514

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.0000226

Gnomad4 OTH exome

AF:

0.0000671

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2023

This variant is present in population databases (rs10411373, gnomAD 0.04%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the AXL protein (p.Ala2Val). This variant has not been reported in the literature in individuals affected with AXL-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.2

DANN

Benign

0.97

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.58

T;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.066

Sift

Benign

0.053

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0070

B;B

Vest4

0.12

MVP

0.53

MPC

0.30

ClinPred

0.0088

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.017

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over