3-49887356-C-A

Variant names:

• chr3-49887356-C-A
• rs137882771
• NM_002447.4:c.4154G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002447.4(MST1R):​c.4154G>T​(p.Gly1385Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,236 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: MST1R NM_002447.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.424

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021238506).
• BS2: High AC in GnomAd4 at 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MST1R	NM_002447.4	c.4154G>T	p.Gly1385Val	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.4154G>T	p.Gly1385Val	missense_variant	Exon 20 of 20	1	NM_002447.4	ENSP00000296474.3

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000640 AC: 161 AN: 251462 Hom.: 0 AF XY: 0.000640 AC XY: 87 AN XY: 135906

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00163 AC: 2382 AN: 1461880 Hom.: 2 Cov.: 30 AF XY: 0.00149 AC XY: 1082 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74510

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.000971

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00125

EpiControl AF: 0.00148

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4154G>T (p.G1385V) alteration is located in exon 20 (coding exon 20) of the MST1R gene. This alteration results from a G to T substitution at nucleotide position 4154, causing the glycine (G) at amino acid position 1385 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MST1R-related disorder Benign:1

Nov 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	0.093
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.8
DANN	Benign	0.90
DEOGEN2	Benign	0.085	T;.;.;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.021	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N;.;.;.;N
REVEL	Benign	0.098
Sift	Benign	0.20	T;.;.;.;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.097	B;.;.;.;.
Vest4		0.16
MVP		0.51
MPC		0.43
ClinPred		0.017	T
GERP RS		3.3
Varity_R		0.082
gMVP		0.34

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: rs137882771; hg19: chr3-49924789;