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.

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.844G>A	p.Ala282Thr	missense splice_region	Exon 5 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.844G>A	p.Ala282Thr	missense splice_region	Exon 5 of 19	ENSP00000295408.4	Q12866
	MERTK	ENST00000439966.5	TSL:1	n.*317G>A		splice_region non_coding_transcript_exon	Exon 5 of 19	ENSP00000402129.1	E9PD22
	MERTK	ENST00000439966.5	TSL:1	n.*317G>A		3_prime_UTR	Exon 5 of 19	ENSP00000402129.1	E9PD22

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 38 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.049	D
Polyphen		0.36	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;