rs35986685

Variant names:

• chr3-49898093-T-G
• rs35986685
• NM_002447.4:c.1838A>C

Variant summary

Our verdict is Benign. The variant received -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 (★★).

• 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:3
• Conservation: PhyloP100: 0.683
• Publications: 13 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=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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1022 AD gene.

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.1838A>C	p.Gln613Pro	missense	Exon 5 of 20	NP_002438.2	Q04912-1
	MST1R	NM_001244937.3		c.1838A>C	p.Gln613Pro	missense	Exon 5 of 19	NP_001231866.1	Q04912-2
	MST1R	NM_001437543.1		c.1838A>C	p.Gln613Pro	missense	Exon 5 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.1838A>C	p.Gln613Pro	missense	Exon 5 of 20	ENSP00000296474.3	Q04912-1
	MST1R	ENST00000621387.4	TSL:1	c.1520A>C	p.Gln507Pro	missense	Exon 3 of 18	ENSP00000482642.1	Q04912-7
	MST1R	ENST00000468525.5	TSL:1	n.1838A>C		non_coding_transcript_exon	Exon 5 of 10

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

GnomAD2 exomes AF: 0.0110 AC: 2758 AN: 251404 AF XY: 0.0134

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 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

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00432 AC: 193 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0476 AC: 4107 AN: 86258

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53342

Middle Eastern (MID) AF: 0.0257 AC: 148 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11408 AN: 1112010

Other (OTH) AF: 0.0116 AC: 703 AN: 60394

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

African (AFR) AF: 0.00192 AC: 80 AN: 41560

American (AMR) AF: 0.00595 AC: 91 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0390 AC: 188 AN: 4826

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00900 AC: 612 AN: 68022

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00880 Hom.: 33

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.68
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Benign	0.23	T
Sift4G	Benign	0.28	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
Mutation Taster		=99/1	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

Other links and lift over

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