rs35986685

chr3-49898093-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002447.4(MST1R):c.1838A>C(p.Gln613Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,098 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts 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.

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 33)
  • Exomes 𝑓: 0.011 (217 hom.)
• Consequence: MST1R NM_002447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.683

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=0.0048924387).
• BP6: Variant 3-49898093-T-G is Benign according to our data. Variant chr3-49898093-T-G is described in ClinVar as [Benign]. Clinvar id is 403115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00671 (1022/152286) while in subpopulation SAS AF= 0.039 (188/4826). AF 95% confidence interval is 0.0344. There are 13 homozygotes in gnomad4. There are 540 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1025 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MST1R	NM_002447.4	c.1838A>C	p.Gln613Pro	missense_variant	5/20	ENST00000296474.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MST1R	ENST00000296474.8	c.1838A>C	p.Gln613Pro	missense_variant	5/20	1	NM_002447.4	P2

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152168 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0389

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00901

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0110 AC: 2758 AN: 251404 Hom.: 40 AF XY: 0.0134 AC XY: 1819 AN XY: 135894

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0483

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00849

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0115 AC: 16787 AN: 1461812 Hom.: 217 Cov.: 32 AF XY: 0.0128 AC XY: 9316 AN XY: 727204

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0476

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00671 AC: 1022 AN: 152286 Hom.: 13 Cov.: 33 AF XY: 0.00725 AC XY: 540 AN XY: 74462

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0390

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00900

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00826 Hom.: 11

Bravo AF: 0.00594

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.0111 AC: 1353

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.00865

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Uncertain	0.32
Sift	Benign	0.23	T;.;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.015	B;.;.
Vest4		0.40
MPC		0.27
ClinPred		0.027	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.85

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: rs35986685; hg19: chr3-49935526; COSMIC: COSV56570117; COSMIC: COSV56570117;