rs786205534
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The ENST00000295408.9(MERTK):c.1604+2T>G variant causes a splice donor change. The variant allele was found at a frequency of 0.000000684 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MERTK
ENST00000295408.9 splice_donor
ENST00000295408.9 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.79
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.051 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of 33, new splice context is: ctgGTattg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-111997478-T-G is Pathogenic according to our data. Variant chr2-111997478-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 191124.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-111997478-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MERTK | NM_006343.3 | c.1604+2T>G | splice_donor_variant | ENST00000295408.9 | NP_006334.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MERTK | ENST00000295408.9 | c.1604+2T>G | splice_donor_variant | 1 | NM_006343.3 | ENSP00000295408 | P1 | |||
MERTK | ENST00000439966.5 | c.*1077+2T>G | splice_donor_variant, NMD_transcript_variant | 1 | ENSP00000402129 | |||||
MERTK | ENST00000409780.5 | c.1076+2T>G | splice_donor_variant | 5 | ENSP00000387277 | |||||
MERTK | ENST00000473065.1 | n.107+2T>G | splice_donor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461246Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726954
GnomAD4 exome
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1461246
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34
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1
AN XY:
726954
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Faculty of Health Sciences, Beirut Arab University | May 23, 2018 | - - |
not provided Pathogenic:1
Likely pathogenic, flagged submission | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | - | - - |
Retinitis pigmentosa 38 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at