2-111898702-G-A

Variant names:

• chr2-111898702-G-A
• rs141412373
• NM_006343.3:c.-34G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006343.3(MERTK):​c.-34G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,599,686 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (75 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (60 hom.)
• Consequence: MERTK NM_006343.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.470

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-111898702-G-A is Benign according to our data. Variant chr2-111898702-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 330739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MERTK	NM_006343.3	c.-34G>A		5_prime_UTR_variant	Exon 1 of 19	ENST00000295408.9	NP_006334.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MERTK	ENST00000295408	c.-34G>A		5_prime_UTR_variant	Exon 1 of 19	1	NM_006343.3	ENSP00000295408.4
MERTK	ENST00000439966.5	n.-34G>A		non_coding_transcript_exon_variant	Exon 1 of 19	1		ENSP00000402129.1
MERTK	ENST00000439966.5	n.-34G>A		5_prime_UTR_variant	Exon 1 of 19	1		ENSP00000402129.1
MERTK	ENST00000409780	c.-141G>A		5_prime_UTR_variant	Exon 1 of 18	5		ENSP00000387277.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2505 AN: 152114 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00409 AC: 894 AN: 218360 Hom.: 29 AF XY: 0.00297 AC XY: 356 AN XY: 119986

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000935

GnomAD4 exome AF: 0.00167 AC: 2420 AN: 1447454 Hom.: 60 Cov.: 31 AF XY: 0.00142 AC XY: 1022 AN XY: 718902

Gnomad4 AFR exome AF: 0.0590

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000155

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000507

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.0164 AC: 2499 AN: 152232 Hom.: 75 Cov.: 31 AF XY: 0.0161 AC XY: 1196 AN XY: 74436

Gnomad4 AFR AF: 0.0570

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00268 Hom.: 2

Bravo AF: 0.0186

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.5
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs141412373; hg19: chr2-112656279; COSMIC: COSV104599941;