rs10496440

Variant names:

• chr2-111907422-A-C
• rs10496440
• NM_006343.3:c.61+8626A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006343.3(MERTK):​c.61+8626A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 152,356 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.054 (288 hom., cov: 33)
• Consequence: MERTK NM_006343.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MERTK	NM_006343.3	MANE Select	c.61+8626A>C		intron	N/A	NP_006334.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MERTK	ENST00000295408.9	TSL:1 MANE Select	c.61+8626A>C		intron	N/A	ENSP00000295408.4
	MERTK	ENST00000439966.5	TSL:1	n.61+8626A>C		intron	N/A	ENSP00000402129.1
	MERTK	ENST00000409780.5	TSL:5	c.-47+8626A>C		intron	N/A	ENSP00000387277.1

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 8205 AN: 152238 Hom.: 289 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0741

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0539 AC: 8205 AN: 152356 Hom.: 288 Cov.: 33 AF XY: 0.0529 AC XY: 3944 AN XY: 74508

African (AFR) AF: 0.0146 AC: 606 AN: 41588

American (AMR) AF: 0.0542 AC: 830 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0277 AC: 134 AN: 4830

European-Finnish (FIN) AF: 0.0544 AC: 578 AN: 10628

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.0804 AC: 5468 AN: 68028

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0594 Hom.: 56

Bravo AF: 0.0525

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.68
PhyloP100		-0.092
Mutation Taster		=100/0	polymorphism (auto)

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: rs10496440; hg19: chr2-112664999;