chr3-49887507-T-C

Position:

• chr3-49887507-T-C

Variant summary

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

The NM_002447.4(MST1R):​c.4003A>G​(p.Arg1335Gly) 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 1,613,852 control chromosomes in the GnomAD database, including 193,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (21115 hom., cov: 33)
  • Exomes 𝑓: 0.47 (172265 hom.)
• Consequence: MST1R NM_002447.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.17

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.538798E-6).
• BP6: Variant 3-49887507-T-C is Benign according to our data. Variant chr3-49887507-T-C is described in ClinVar as [Benign]. Clinvar id is 3058886.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MST1R	NM_002447.4	c.4003A>G	p.Arg1335Gly	missense_variant	20/20	ENST00000296474.8	NP_002438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MST1R	ENST00000296474.8	c.4003A>G	p.Arg1335Gly	missense_variant	20/20	1	NM_002447.4	ENSP00000296474	P2
MST1R	ENST00000621387.4	c.3685A>G	p.Arg1229Gly	missense_variant	18/18	1		ENSP00000482642
MST1R	ENST00000344206.8	c.3856A>G	p.Arg1286Gly	missense_variant	19/19	5		ENSP00000341325	A2
MST1R	ENST00000411578.6	c.*825A>G		3_prime_UTR_variant, NMD_transcript_variant	19/19	5		ENSP00000407926

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77240 AN: 151986 Hom.: 21084 Cov.: 33

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.500

GnomAD3 exomes AF: 0.408 AC: 102561 AN: 251134 Hom.: 23564 AF XY: 0.405 AC XY: 54987 AN XY: 135768

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.147

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: 694059 AN: 1461748 Hom.: 172265 Cov.: 55 AF XY: 0.468 AC XY: 340628 AN XY: 727178

Gnomad4 AFR exome AF: 0.683

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: 0.508 AC: 77320 AN: 152104 Hom.: 21115 Cov.: 33 AF XY: 0.493 AC XY: 36679 AN XY: 74360

Gnomad4 AFR AF: 0.678

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.504

Alfa AF: 0.489 Hom.: 36901

Bravo AF: 0.524

TwinsUK AF: 0.517 AC: 1917

ALSPAC AF: 0.519 AC: 2002

ESP6500AA AF: 0.674 AC: 2969

ESP6500EA AF: 0.506 AC: 4352

ExAC AF: 0.417 AC: 50694

Asia WGS AF: 0.291 AC: 1012 AN: 3478

EpiCase AF: 0.498

EpiControl AF: 0.497

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MST1R-related disorder Benign:1

Benign, no assertion criteria provided

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.020
DANN	Benign	0.16
DEOGEN2	Benign	0.16	T;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.13	T;T;T;T;T
MetaRNN	Benign	0.0000035	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L;.;.;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.39	N;.;.;.;N
REVEL	Benign	0.11
Sift	Benign	0.51	T;.;.;.;T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.057
MPC		0.23
ClinPred		0.0060	T
GERP RS		-4.2
Varity_R		0.17
gMVP		0.46

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: rs1062633; hg19: chr3-49924940; COSMIC: COSV56566222; COSMIC: COSV56566222;