chr3-49887507-T-C

Variant names:

• chr3-49887507-T-C
• rs1062633
• NM_002447.4:c.4003A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MST1R	NM_002447.4	c.4003A>G	p.Arg1335Gly	missense_variant	Exon 20 of 20	ENST00000296474.8	NP_002438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MST1R	ENST00000296474.8	c.4003A>G	p.Arg1335Gly	missense_variant	Exon 20 of 20	1	NM_002447.4	ENSP00000296474.3

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

GnomAD2 exomes AF: 0.408 AC: 102561 AN: 251134 AF XY: 0.405

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 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 AC: 22878 AN: 33478

Gnomad4 AMR exome AF: 0.303 AC: 13557 AN: 44712

Gnomad4 ASJ exome AF: 0.405 AC: 10594 AN: 26136

Gnomad4 EAS exome AF: 0.153 AC: 6082 AN: 39668

Gnomad4 SAS exome AF: 0.241 AC: 20780 AN: 86258

Gnomad4 FIN exome AF: 0.390 AC: 20841 AN: 53384

Gnomad4 NFE exome AF: 0.511 AC: 568659 AN: 1111952

Gnomad4 Remaining exome AF: 0.467 AC: 28221 AN: 60392

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 AC: 0.67784 AN: 0.67784

Gnomad4 AMR AF: 0.398 AC: 0.397906 AN: 0.397906

Gnomad4 ASJ AF: 0.394 AC: 0.393721 AN: 0.393721

Gnomad4 EAS AF: 0.142 AC: 0.141863 AN: 0.141863

Gnomad4 SAS AF: 0.235 AC: 0.23477 AN: 0.23477

Gnomad4 FIN AF: 0.384 AC: 0.383582 AN: 0.383582

Gnomad4 NFE AF: 0.502 AC: 0.502192 AN: 0.502192

Gnomad4 OTH AF: 0.504 AC: 0.503788 AN: 0.503788

Alfa AF: 0.495 Hom.: 74749

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

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.;.;.
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
Mutation Taster		=92/8	polymorphism (auto)

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;