2-111994404-G-C

Variant names:

• chr2-111994404-G-C
• NM_006343.3:c.1450G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_006343.3(MERTK):​c.1450G>C​(p.Gly484Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G484S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MERTK NM_006343.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.37

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-111994404-G-A is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MERTK	NM_006343.3	c.1450G>C	p.Gly484Arg	missense_variant, splice_region_variant	Exon 9 of 19	ENST00000295408.9	NP_006334.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MERTK	ENST00000295408.9	c.1450G>C	p.Gly484Arg	missense_variant, splice_region_variant	Exon 9 of 19	1	NM_006343.3	ENSP00000295408.4
MERTK	ENST00000439966.5	n.*923G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 19	1		ENSP00000402129.1
MERTK	ENST00000439966.5	n.*923G>C		3_prime_UTR_variant	Exon 9 of 19	1		ENSP00000402129.1
MERTK	ENST00000409780.5	c.922G>C	p.Gly308Arg	missense_variant, splice_region_variant	Exon 8 of 18	5		ENSP00000387277.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.54	D;D;T;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.5	M;M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.052	T;T;.;T
Sift4G	Benign	0.15	T;T;D;T
Polyphen		0.99	D;D;.;.
Vest4		0.36
MutPred		0.47		Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);.;.;
MVP		0.89
MPC		0.63
ClinPred		0.87	D
GERP RS		4.1
Varity_R		0.038
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: 16
DS_DL_spliceai		0.73		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-112751981;