2-112022343-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_006343.3(MERTK):c.2435A>G(p.Tyr812Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y812S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

MERTK
NM_006343.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

MERTK (HGNC:7027): (MER proto-oncogene, tyrosine kinase) This gene is a member of the MER/AXL/TYRO3 receptor kinase family and encodes a transmembrane protein with two fibronectin type-III domains, two Ig-like C2-type (immunoglobulin-like) domains, and one tyrosine kinase domain. Mutations in this gene have been associated with disruption of the retinal pigment epithelium (RPE) phagocytosis pathway and onset of autosomal recessive retinitis pigmentosa (RP). [provided by RefSeq, Jul 2008]

MERTK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a domain Protein kinase (size 271) in uniprot entity MERTK_HUMAN there are 24 pathogenic changes around while only 6 benign (80%) in NM_006343.3

BP4

Computational evidence support a benign effect (MetaRNN=0.20418027).

BP6

Variant 2-112022343-A-G is Benign according to our data. Variant chr2-112022343-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1562508.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MERTK	NM_006343.3 link	c.2435A>G	p.Tyr812Cys	missense_variant	Exon 18 of 19	ENST00000295408.9	NP_006334.2	Q12866

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MERTK	ENST00000295408.9 link	c.2435A>G	p.Tyr812Cys	missense_variant	Exon 18 of 19	1	NM_006343.3	ENSP00000295408.4		Q12866

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000414

AC:

104

AN:

251490

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000211

AC:

308

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

152

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00270

Gnomad4 NFE exome

AF:

0.0000836

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000453

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000876

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000395

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinal dystrophy

Uncertain:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MERTK-related disorder

Benign:1

Sep 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D;T;D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

.;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

2.0

M;M;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-8.7

D;D;.;D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.83

MVP

0.96

MPC

0.67

ClinPred

0.62

GERP RS

5.4

Varity_R

0.91

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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