2-111965277-G-T

Variant names:

• chr2-111965277-G-T
• rs7588635
• NM_006343.3:c.844G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006343.3(MERTK):​c.844G>T​(p.Ala282Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. A282T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MERTK NM_006343.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94
• Publications: 14 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MERTK	NM_006343.3	c.844G>T	p.Ala282Ser	missense_variant, splice_region_variant	Exon 5 of 19	ENST00000295408.9	NP_006334.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MERTK	ENST00000295408.9	c.844G>T	p.Ala282Ser	missense_variant, splice_region_variant	Exon 5 of 19	1	NM_006343.3	ENSP00000295408.4
MERTK	ENST00000439966.5	n.*317G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 19	1		ENSP00000402129.1
MERTK	ENST00000439966.5	n.*317G>T		3_prime_UTR_variant	Exon 5 of 19	1		ENSP00000402129.1
MERTK	ENST00000409780.5	c.316G>T	p.Ala106Ser	missense_variant, splice_region_variant	Exon 4 of 18	5		ENSP00000387277.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;M;.
PhyloP100		5.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.097
Sift	Uncertain	0.021	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.36	B;B;.
Vest4		0.24
MutPred		0.30		Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);.;
MVP		0.69
MPC		0.19
ClinPred		0.78	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.18
gMVP		0.40
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7588635; hg19: chr2-112722854; COSMIC: COSV107334031;