2-111898794-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006343.3(MERTK):c.59G>C(p.Arg20Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,593,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MERTK NM_006343.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002070
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09375551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MERTK	NM_006343.3	c.59G>C	p.Arg20Thr	missense_variant, splice_region_variant	1/19	ENST00000295408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MERTK	ENST00000295408.9	c.59G>C	p.Arg20Thr	missense_variant, splice_region_variant	1/19	1	NM_006343.3	P1
MERTK	ENST00000439966.5	c.59G>C	p.Arg20Thr	missense_variant, splice_region_variant, NMD_transcript_variant	1/19	1
MERTK	ENST00000409780.5	c.-49G>C		splice_region_variant, 5_prime_UTR_variant	1/18	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1440952 Hom.: 0 Cov.: 31 AF XY: 0.0000224 AC XY: 16 AN XY: 714824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000193

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152320 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000851 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 16714263). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 20 of the MERTK protein (p.Arg20Thr). ClinVar contains an entry for this variant (Variation ID: 1436276). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine 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	0.082
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	2.9
Dann	Benign	0.61
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.10	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.18	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0	B;B
Vest4		0.70
MutPred		0.71		Loss of phosphorylation at T23 (P = 0.0791);Loss of phosphorylation at T23 (P = 0.0791);
MVP		0.65
MPC		0.20
ClinPred		0.038	T
GERP RS		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs552509122; hg19: chr2-112656371;