Genetic Variant NM_006343.3:c.56G>A (chr2-111898791-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006343.3(MERTK):c.56G>A(p.Arg19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MERTK
NM_006343.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0570

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

MERTK-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa 38
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MERTK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12431377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006343.3. 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
	MERTK	NM_006343.3	MANE Select	c.56G>A	p.Arg19His	missense	Exon 1 of 19	NP_006334.2	Q12866

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MERTK	ENST00000295408.9	TSL:1 MANE Select	c.56G>A	p.Arg19His	missense	Exon 1 of 19	ENSP00000295408.4	Q12866
MERTK	ENST00000439966.5	TSL:1	n.56G>A		non_coding_transcript_exon	Exon 1 of 19	ENSP00000402129.1	E9PD22
MERTK	ENST00000953051.1		c.56G>A	p.Arg19His	missense	Exon 1 of 18	ENSP00000623110.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

198580

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1441298

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715070

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33098

American (AMR)

AF:

0.0000237

AC:

AN:

42144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25644

East Asian (EAS)

AF:

0.00

AC:

AN:

38782

South Asian (SAS)

AF:

0.00

AC:

AN:

83068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102916

Other (OTH)

AF:

0.00

AC:

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

PhyloP100

-0.057

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.060

REVEL

Benign

0.12

Sift

Benign

0.067

Sift4G

Benign

0.61

Polyphen

0.80

Vest4

0.064

MutPred

0.36

Gain of sheet (P = 0.0344)

MVP

0.77

MPC

0.17

ClinPred

0.093

GERP RS

-0.91

PromoterAI

-0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.030

gMVP

0.20

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over