3-49898669-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002447.4(MST1R):c.1568A>G(p.Gln523Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,613,800 control chromosomes in the GnomAD database, including 192,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q523E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.51 (20913 hom., cov: 34)
  • Exomes 𝑓: 0.47 (172036 hom.)
• Consequence: MST1R NM_002447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.968

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.325076E-6).
• BP6: Variant 3-49898669-T-C is Benign according to our data. Variant chr3-49898669-T-C is described in ClinVar as [Benign]. Clinvar id is 1237612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MST1R	NM_002447.4	c.1568A>G	p.Gln523Arg	missense_variant	4/20	ENST00000296474.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MST1R	ENST00000296474.8	c.1568A>G	p.Gln523Arg	missense_variant	4/20	1	NM_002447.4	P2

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76985 AN: 152036 Hom.: 20883 Cov.: 34

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.501

GnomAD3 exomes AF: 0.408 AC: 102273 AN: 250958 Hom.: 23417 AF XY: 0.404 AC XY: 54858 AN XY: 135692

Gnomad AFR exome AF: 0.677

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.475 AC: 693707 AN: 1461646 Hom.: 172036 Cov.: 65 AF XY: 0.468 AC XY: 340478 AN XY: 727128

Gnomad4 AFR exome AF: 0.676

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.511

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.506 AC: 77063 AN: 152154 Hom.: 20913 Cov.: 34 AF XY: 0.491 AC XY: 36564 AN XY: 74396

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.504

Alfa AF: 0.488 Hom.: 36075

Bravo AF: 0.521

TwinsUK AF: 0.517 AC: 1916

ALSPAC AF: 0.520 AC: 2003

ESP6500AA AF: 0.667 AC: 2941

ESP6500EA AF: 0.506 AC: 4350

ExAC AF: 0.417 AC: 50578

Asia WGS AF: 0.290 AC: 1010 AN: 3478

EpiCase AF: 0.498

EpiControl AF: 0.497

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MST1R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.0050
Dann	Benign	0.45
DEOGEN2	Benign	0.066	T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.060	T;T;T
MetaRNN	Benign	0.0000023	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.13	N;.;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.48	N;.;N
REVEL	Benign	0.026
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.019
MPC		0.20
ClinPred		0.0063	T
GERP RS		-6.8
Varity_R		0.037
gMVP		0.53

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: rs2230590; hg19: chr3-49936102; COSMIC: COSV56566654; COSMIC: COSV56566654;