2-111898795-A-T

Position:

chr2-111898795-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_006343.3(MERTK):c.60A>T(p.Arg20Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 1,591,892 control chromosomes in the GnomAD database, including 1,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R20T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.033 ( 121 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1569 hom. )

Consequence

MERTK
NM_006343.3 missense, splice_region

Scores

Splicing: ADA: 0.08806

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: 0.757

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017398).

BP6

Variant 2-111898795-A-T is Benign according to our data. Variant chr2-111898795-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95372.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=1, Benign=2}.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MERTK	NM_006343.3 linkuse as main transcript	c.60A>T	p.Arg20Ser	missense_variant, splice_region_variant	1/19	ENST00000295408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MERTK	ENST00000295408.9 linkuse as main transcript	c.60A>T	p.Arg20Ser	missense_variant, splice_region_variant	1/19	1	NM_006343.3	P1
MERTK	ENST00000439966.5 linkuse as main transcript	c.60A>T	p.Arg20Ser	missense_variant, splice_region_variant, NMD_transcript_variant	1/19	1
MERTK	ENST00000409780.5 linkuse as main transcript	c.-48A>T		splice_region_variant, 5_prime_UTR_variant	1/18	5

Frequencies

GnomAD3 genomes

AF:

0.0332

AC:

5051

AN:

152048

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00818

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0273

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0275

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0369

AC:

7296

AN:

197584

Hom.:

205

AF XY:

0.0374

AC XY:

4077

AN XY:

108870

show subpopulations

Gnomad AFR exome

AF:

0.00668

Gnomad AMR exome

AF:

0.0264

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0144

Gnomad FIN exome

AF:

0.0344

Gnomad NFE exome

AF:

0.0494

Gnomad OTH exome

AF:

0.0522

GnomAD4 exome

AF:

0.0414

AC:

59623

AN:

1439726

Hom.:

1569

Cov.:

AF XY:

0.0413

AC XY:

29460

AN XY:

714086

show subpopulations

Gnomad4 AFR exome

AF:

0.00720

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.123

Gnomad4 EAS exome

AF:

0.0000775

Gnomad4 SAS exome

AF:

0.0147

Gnomad4 FIN exome

AF:

0.0291

Gnomad4 NFE exome

AF:

0.0448

Gnomad4 OTH exome

AF:

0.0454

GnomAD4 genome

AF:

0.0332

AC:

5046

AN:

152166

Hom.:

121

Cov.:

AF XY:

0.0313

AC XY:

2330

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00816

Gnomad4 AMR

AF:

0.0272

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.000582

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.0275

Gnomad4 NFE

AF:

0.0495

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0523

Hom.:

Bravo

AF:

0.0332

TwinsUK

AF:

0.0426

AC:

158

ALSPAC

AF:

0.0389

AC:

150

ESP6500AA

AF:

0.00701

AC:

ESP6500EA

AF:

0.0490

AC:

408

ExAC

AF:

0.0307

AC:

3599

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Retinitis pigmentosa 38

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jan 01, 2021

Class 3 ACMG Guidelines, 2015 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 20, 2013

- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.31

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.076

Sift

Benign

0.17

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0090

B;B

Vest4

0.077

MutPred

0.26

Gain of phosphorylation at R20 (P = 0.0876);Gain of phosphorylation at R20 (P = 0.0876);

MPC

0.15

ClinPred

0.0027

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.064

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.088

dbscSNV1_RF

Benign

0.37

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

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