3-49887468-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002447.4(MST1R):c.4042C>A(p.Leu1348Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: MST1R NM_002447.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35660797).
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MST1R	NM_002447.4	c.4042C>A	p.Leu1348Met	missense_variant	20/20	ENST00000296474.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MST1R	ENST00000296474.8	c.4042C>A	p.Leu1348Met	missense_variant	20/20	1	NM_002447.4	P2
MST1R	ENST00000621387.4	c.3724C>A	p.Leu1242Met	missense_variant	18/18	1
MST1R	ENST00000344206.8	c.3895C>A	p.Leu1299Met	missense_variant	19/19	5		A2
MST1R	ENST00000411578.6	c.*864C>A		3_prime_UTR_variant, NMD_transcript_variant	19/19	5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251446 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74380

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.4042C>A (p.L1348M) alteration is located in exon 20 (coding exon 20) of the MST1R gene. This alteration results from a C to A substitution at nucleotide position 4042, causing the leucine (L) at amino acid position 1348 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Uncertain	0.037	D
MutationAssessor	Benign	1.8	L;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;.;.;.;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D;.;.;.;D
Sift4G	Uncertain	0.017	D;T;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.30
MutPred		0.45		Loss of catalytic residue at L1348 (P = 0.0109);.;.;.;.;
MVP		0.74
MPC		0.72
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.67
gMVP		0.66

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: rs779416241; hg19: chr3-49924901;