2-112022343-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP3BS1_Supporting

The NM_006343.3(MERTK):c.2435A>C(p.Tyr812Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y812C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

MERTK
NM_006343.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a domain Protein kinase (size 271) in uniprot entity MERTK_HUMAN there are 43 pathogenic changes around while only 9 benign (83%) in NM_006343.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000301 (44/1461890) while in subpopulation MID AF = 0.00329 (19/5768). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MERTK	NM_006343.3 link	c.2435A>C	p.Tyr812Ser	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>C	p.Tyr812Ser	missense_variant	Exon 18 of 19	1	NM_006343.3	ENSP00000295408.4		Q12866

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.0000596

AC:

AN:

251490

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000201

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.00000719

AC:

AN:

1112008

Gnomad4 Remaining exome

AF:

0.0000993

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000788

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000523

AC:

0.000522534

AN:

0.000522534

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00142

AC:

0.00142045

AN:

0.00142045

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000169

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jan 12, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 02, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in an individual with Leber congenital amaurosis who also harbored a homozygous pathogenic variant in another gene responsible for this phenotype (Eisenberger et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24265693) -

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 812 of the MERTK protein (p.Tyr812Ser). This variant is present in population databases (rs141361084, gnomAD 0.02%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 24265693). ClinVar contains an entry for this variant (Variation ID: 403082). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MERTK protein function. 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. -

Retinitis pigmentosa 38

Uncertain:2

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with RP - not related to our patient's phenotype. This variant is reported in one individual with Leber congenital amaurosis who carreid a homozygous frameshift variant in another RP gen- RPGRIP1 (Eisenberger_2013_24265693). -

Retinal dystrophy

Uncertain:1

Jan 01, 2020

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;D;T;D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.79

D;D;D;D;D

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.4

L;L;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-8.7

D;D;.;D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.79

MutPred

0.61

Gain of disorder (P = 0.0075);Gain of disorder (P = 0.0075);.;.;.;

MVP

0.94

MPC

0.72

ClinPred

0.78

GERP RS

5.4

Varity_R

0.95

gMVP

0.89

Mutation Taster

=12/88

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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