3-49890005-C-A

Variant names:

• chr3-49890005-C-A
• rs1414519759
• NM_002447.4:c.3866G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002447.4(MST1R):​c.3866G>T​(p.Arg1289Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MST1R NM_002447.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

MST1R (HGNC:7381): (macrophage stimulating 1 receptor) This gene encodes a cell surface receptor for macrophage-stimulating protein (MSP) with tyrosine kinase activity. The mature form of this protein is a heterodimer of disulfide-linked alpha and beta subunits, generated by proteolytic cleavage of a single-chain precursor. The beta subunit undergoes tyrosine phosphorylation upon stimulation by MSP. This protein is expressed on the ciliated epithelia of the mucociliary transport apparatus of the lung, and together with MSP, thought to be involved in host defense. Alternative splicing generates multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23284447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MST1R	NM_002447.4	c.3866G>T	p.Arg1289Leu	missense_variant	Exon 19 of 20	ENST00000296474.8	NP_002438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MST1R	ENST00000296474.8	c.3866G>T	p.Arg1289Leu	missense_variant	Exon 19 of 20	1	NM_002447.4	ENSP00000296474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250534 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461442 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3866G>T (p.R1289L) alteration is located in exon 19 (coding exon 19) of the MST1R gene. This alteration results from a G to T substitution at nucleotide position 3866, causing the arginine (R) at amino acid position 1289 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.82	L;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;.;.;N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.0010	B;.;.;.
Vest4		0.26
MutPred		0.56		Loss of disorder (P = 0.2165);.;.;.;
MVP		0.47
MPC		0.23
ClinPred		0.75	D
GERP RS		4.0
Varity_R		0.49
gMVP		0.78

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: rs1414519759; hg19: chr3-49927438;