rs4374383

Variant names:

• chr2-112013193-A-G
• rs4374383
• NM_006343.3:c.2079+3127A>G

Variant summary

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

The NM_006343.3(MERTK):​c.2079+3127A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 153,820 control chromosomes in the GnomAD database, including 26,210 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 0.58 (25816 hom., cov: 29)
  • Exomes 𝑓: 0.61 (394 hom.)
• Consequence: MERTK NM_006343.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 74 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.606 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MERTK	NM_006343.3	MANE Select	c.2079+3127A>G		intron	N/A	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.2079+3127A>G		intron	N/A	ENSP00000295408.4	Q12866
	MERTK	ENST00000439966.5	TSL:1	n.*1552+3127A>G		intron	N/A	ENSP00000402129.1	E9PD22
	MERTK	ENST00000953051.1		c.1998+3127A>G		intron	N/A	ENSP00000623110.1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 87780 AN: 151646 Hom.: 25798 Cov.: 29

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.596

GnomAD4 exome AF: 0.612 AC: 1258 AN: 2056 Hom.: 394 Cov.: 0 AF XY: 0.598 AC XY: 614 AN XY: 1026

African (AFR) AF: 0.614 AC: 43 AN: 70

American (AMR) AF: 0.750 AC: 6 AN: 8

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4 AN: 4

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.670 AC: 59 AN: 88

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.613 AC: 928 AN: 1514

European-Non Finnish (NFE) AF: 0.620 AC: 119 AN: 192

Other (OTH) AF: 0.551 AC: 98 AN: 178

GnomAD4 genome AF: 0.579 AC: 87838 AN: 151764 Hom.: 25816 Cov.: 29 AF XY: 0.580 AC XY: 43013 AN XY: 74120

African (AFR) AF: 0.525 AC: 21689 AN: 41350

American (AMR) AF: 0.598 AC: 9124 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2263 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1420 AN: 5130

South Asian (SAS) AF: 0.605 AC: 2891 AN: 4778

European-Finnish (FIN) AF: 0.670 AC: 7052 AN: 10532

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41505 AN: 67926

Other (OTH) AF: 0.598 AC: 1262 AN: 2112

Alfa AF: 0.594 Hom.: 85588

Bravo AF: 0.568

Asia WGS AF: 0.469 AC: 1633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.70
PhyloP100		-0.042
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4374383;

hg19: chr2-112770770;

COSMIC: COSV107333968;