2-111898795-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006343.3(MERTK):c.60A>T(p.Arg20Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 1,591,892 control chromosomes in the GnomAD database, including 1,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (121 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1569 hom.)
• Consequence: MERTK NM_006343.3 missense, splice_region
• Scores: Splicing: ADA: 0.08806
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 0.757

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017398).
• BP6: Variant 2-111898795-A-T is Benign according to our data. Variant chr2-111898795-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95372.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, not_provided=1, Benign=2}.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MERTK	NM_006343.3	c.60A>T	p.Arg20Ser	missense_variant, splice_region_variant	1/19	ENST00000295408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MERTK	ENST00000295408.9	c.60A>T	p.Arg20Ser	missense_variant, splice_region_variant	1/19	1	NM_006343.3	P1
MERTK	ENST00000439966.5	c.60A>T	p.Arg20Ser	missense_variant, splice_region_variant, NMD_transcript_variant	1/19	1
MERTK	ENST00000409780.5	c.-48A>T		splice_region_variant, 5_prime_UTR_variant	1/18	5

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5051 AN: 152048 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0369 AC: 7296 AN: 197584 Hom.: 205 AF XY: 0.0374 AC XY: 4077 AN XY: 108870

Gnomad AFR exome AF: 0.00668

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0144

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0494

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0414 AC: 59623 AN: 1439726 Hom.: 1569 Cov.: 31 AF XY: 0.0413 AC XY: 29460 AN XY: 714086

Gnomad4 AFR exome AF: 0.00720

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.0000775

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.0291

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0454

GnomAD4 genome AF: 0.0332 AC: 5046 AN: 152166 Hom.: 121 Cov.: 32 AF XY: 0.0313 AC XY: 2330 AN XY: 74396

Gnomad4 AFR AF: 0.00816

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0275

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0523 Hom.: 93

Bravo AF: 0.0332

TwinsUK AF: 0.0426 AC: 158

ALSPAC AF: 0.0389 AC: 150

ESP6500AA AF: 0.00701 AC: 29

ESP6500EA AF: 0.0490 AC: 408

ExAC AF: 0.0307 AC: 3599

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Retinitis pigmentosa 38 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jan 01, 2021

Class 3 ACMG Guidelines, 2015 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 20, 2013

- -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Benign	0.78
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.57	D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.076
Sift	Benign	0.17	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0090	B;B
Vest4		0.077
MutPred		0.26		Gain of phosphorylation at R20 (P = 0.0876);Gain of phosphorylation at R20 (P = 0.0876);
MPC		0.15
ClinPred		0.0027	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.064
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.088
dbscSNV1_RF	Benign	0.37
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35898499; hg19: chr2-112656372; COSMIC: COSV54924029;