rs541717028

Variant names:

• chr2-112019497-C-G
• rs541717028
• NM_006343.3:c.2164C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-112019497-C-G
• chr2-112019497-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_006343.3(MERTK):​c.2164C>G​(p.Arg722Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R722Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MERTK NM_006343.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.43
• Publications: 7 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006343.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 2-112019497-C-G is Pathogenic according to our data. Variant chr2-112019497-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 866123.

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.2164C>G	p.Arg722Gly	missense	Exon 16 of 19	NP_006334.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MERTK	ENST00000295408.9	TSL:1 MANE Select	c.2164C>G	p.Arg722Gly	missense	Exon 16 of 19	ENSP00000295408.4
	MERTK	ENST00000439966.5	TSL:1	n.*1637C>G		non_coding_transcript_exon	Exon 16 of 19	ENSP00000402129.1
	MERTK	ENST00000439966.5	TSL:1	n.*1637C>G		3_prime_UTR	Exon 16 of 19	ENSP00000402129.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.81		Gain of catalytic residue at R722 (P = 0.0291)
MVP		0.89
MPC		0.66
ClinPred		0.96	D
GERP RS		3.5
PromoterAI		-0.11	Neutral
Varity_R		0.87
gMVP		0.92
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs541717028; hg19: chr2-112777074;