rs7588635

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-111965277-G-A
• chr2-111965277-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PP3_Strong BP6_Very_Strong BA1

The NM_006343.3(MERTK):​c.844G>A​(p.Ala282Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00831 in 1,614,026 control chromosomes in the GnomAD database, including 939 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A282A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.043 (487 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (452 hom.)
• Consequence: MERTK NM_006343.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -12 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-111965277-G-A is Benign according to our data. Variant chr2-111965277-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MERTK	NM_006343.3	c.844G>A	p.Ala282Thr	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>A	p.Ala282Thr	missense_variant, splice_region_variant	Exon 5 of 19	1	NM_006343.3	ENSP00000295408.4
MERTK	ENST00000439966.5	n.*317G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 19	1		ENSP00000402129.1
MERTK	ENST00000439966.5	n.*317G>A		3_prime_UTR_variant	Exon 5 of 19	1		ENSP00000402129.1
MERTK	ENST00000409780.5	c.316G>A	p.Ala106Thr	missense_variant, splice_region_variant	Exon 4 of 18	5		ENSP00000387277.1

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6578 AN: 152126 Hom.: 487 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0111 AC: 2791 AN: 251316 AF XY: 0.00812

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00833

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00467 AC: 6825 AN: 1461782 Hom.: 452 Cov.: 30 AF XY: 0.00410 AC XY: 2978 AN XY: 727194

African (AFR) AF: 0.155 AC: 5198 AN: 33478

American (AMR) AF: 0.00901 AC: 403 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5768

European-Non Finnish (NFE) AF: 0.000389 AC: 432 AN: 1111940

Other (OTH) AF: 0.0109 AC: 658 AN: 60384

GnomAD4 genome AF: 0.0433 AC: 6589 AN: 152244 Hom.: 487 Cov.: 32 AF XY: 0.0418 AC XY: 3112 AN XY: 74438

African (AFR) AF: 0.150 AC: 6228 AN: 41500

American (AMR) AF: 0.0159 AC: 243 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68034

Other (OTH) AF: 0.0355 AC: 75 AN: 2112

Alfa AF: 0.0169 Hom.: 592

Bravo AF: 0.0492

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.136 AC: 598

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0136 AC: 1646

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 38 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.62
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;.
PhyloP100		5.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.049	D;D;T
Polyphen		0.36	B;B;.
Vest4		0.23
MPC		0.20
ClinPred		0.029	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.21
gMVP		0.39
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.010		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;