rs863224894

chr2-112021424-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_006343.3(MERTK):c.2192T>C(p.Leu731Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L731L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MERTK NM_006343.3 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_006343.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 2-112021424-T-C is Pathogenic according to our data. Variant chr2-112021424-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MERTK	NM_006343.3	c.2192T>C	p.Leu731Ser	missense_variant, splice_region_variant	17/19	ENST00000295408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MERTK	ENST00000295408.9	c.2192T>C	p.Leu731Ser	missense_variant, splice_region_variant	17/19	1	NM_006343.3	P1
MERTK	ENST00000439966.5	c.*1665T>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	17/19	1
MERTK	ENST00000409780.5	c.1664T>C	p.Leu555Ser	missense_variant, splice_region_variant	16/18	5
MERTK	ENST00000449344.2	c.164T>C	p.Leu55Ser	missense_variant, splice_region_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 38 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Sep 10, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;T;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D;D;.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.99
MutPred		0.81		Gain of catalytic residue at L731 (P = 0.0095);Gain of catalytic residue at L731 (P = 0.0095);.;.;.;
MVP		0.98
MPC		0.71
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs863224894; hg19: chr2-112779001;