chr3-49898669-T-C

Variant names:

• chr3-49898669-T-C
• rs2230590
• NM_002447.4:c.1568A>G
• MST1R p.Gln523Arg

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q523P) 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:3
• Conservation: PhyloP100: -0.968
• Publications: 73 publications found

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]

MST1R Gene-Disease associations (from GenCC):

• nasopharyngeal carcinoma, susceptibility to, 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MST1R	NM_002447.4	MANE Select	c.1568A>G	p.Gln523Arg	missense	Exon 4 of 20	NP_002438.2	Q04912-1
	MST1R	NM_001244937.3		c.1568A>G	p.Gln523Arg	missense	Exon 4 of 19	NP_001231866.1	Q04912-2
	MST1R	NM_001437543.1		c.1568A>G	p.Gln523Arg	missense	Exon 4 of 19	NP_001424472.1	H7C074

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MST1R	ENST00000296474.8	TSL:1 MANE Select	c.1568A>G	p.Gln523Arg	missense	Exon 4 of 20	ENSP00000296474.3	Q04912-1
	MST1R	ENST00000621387.4	TSL:1	c.1250A>G	p.Gln417Arg	missense	Exon 2 of 18	ENSP00000482642.1	Q04912-7
	MST1R	ENST00000468525.5	TSL:1	n.1568A>G		non_coding_transcript_exon	Exon 4 of 10

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

GnomAD2 exomes AF: 0.408 AC: 102273 AN: 250958 AF XY: 0.404

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 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

African (AFR) AF: 0.676 AC: 22625 AN: 33480

American (AMR) AF: 0.303 AC: 13529 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10586 AN: 26124

East Asian (EAS) AF: 0.153 AC: 6076 AN: 39684

South Asian (SAS) AF: 0.241 AC: 20773 AN: 86246

European-Finnish (FIN) AF: 0.390 AC: 20795 AN: 53290

Middle Eastern (MID) AF: 0.424 AC: 2444 AN: 5766

European-Non Finnish (NFE) AF: 0.511 AC: 568692 AN: 1111954

Other (OTH) AF: 0.467 AC: 28187 AN: 60390

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

African (AFR) AF: 0.670 AC: 27842 AN: 41526

American (AMR) AF: 0.398 AC: 6084 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3470

East Asian (EAS) AF: 0.143 AC: 734 AN: 5132

South Asian (SAS) AF: 0.234 AC: 1130 AN: 4830

European-Finnish (FIN) AF: 0.384 AC: 4066 AN: 10596

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34149 AN: 67992

Other (OTH) AF: 0.504 AC: 1064 AN: 2110

Alfa AF: 0.494 Hom.: 52661

Bravo AF: 0.521

Asia WGS AF: 0.290 AC: 1010 AN: 3478

EpiCase AF: 0.498

EpiControl AF: 0.497

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MST1R-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.13	N
PhyloP100		-0.97
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.037
gMVP		0.53
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2230590;

hg19: chr3-49936102;

COSMIC: COSV56566654;

COSMIC: COSV56566654;