chr2-111898769-C-T

Variant names:

• chr2-111898769-C-T
• rs755593299
• NM_006343.3:c.34C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006343.3(MERTK):​c.34C>T​(p.Leu12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MERTK NM_006343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.191
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051656514).

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.34C>T	p.Leu12Phe	missense	Exon 1 of 19	NP_006334.2	Q12866

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MERTK	ENST00000295408.9	TSL:1 MANE Select	c.34C>T	p.Leu12Phe	missense	Exon 1 of 19	ENSP00000295408.4	Q12866
	MERTK	ENST00000439966.5	TSL:1	n.34C>T		non_coding_transcript_exon	Exon 1 of 19	ENSP00000402129.1	E9PD22
	MERTK	ENST00000953051.1		c.34C>T	p.Leu12Phe	missense	Exon 1 of 18	ENSP00000623110.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000185 AC: 4 AN: 216340 AF XY: 0.00000839

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000920

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450684 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720676

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.0000229 AC: 1 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.00 AC: 0 AN: 84320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107500

Other (OTH) AF: 0.00 AC: 0 AN: 59834

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.22	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.67	N
PhyloP100		0.19
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.14
Sift	Benign	0.28	T
Sift4G	Benign	0.19	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.21		Loss of helix (P = 0.0558)
MVP		0.31
MPC		0.14
ClinPred		0.018	T
GERP RS		-0.030
PromoterAI		-0.23	Neutral
Varity_R		0.051
gMVP		0.19
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs755593299; hg19: chr2-112656346;