NM_020998.4:c.1966G>T

Variant names:

• chr3-49684364-C-A
• rs199810403
• NM_020998.4:c.1966G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020998.4(MST1):​c.1966G>T​(p.Glu656*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,460,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MST1 NM_020998.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 0 publications found

Genes affected

MST1 (HGNC:7380): (macrophage stimulating 1) The protein encoded by this gene contains four kringle domains and a serine protease domain, similar to that found in hepatic growth factor. Despite the presence of the serine protease domain, the encoded protein may not have any proteolytic activity. The receptor for this protein is RON tyrosine kinase, which upon activation stimulates ciliary motility of ciliated epithelial lung cells. This protein is secreted and cleaved to form an alpha chain and a beta chain bridged by disulfide bonds. [provided by RefSeq, Jan 2010]

MST1 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to STK4 deficiency

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: Unknown Classification: MODERATE Submitted by: Genomics England PanelApp

ENSG00000259970 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020998.4. 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
	MST1	NM_020998.4	MANE Select	c.1966G>T	p.Glu656*	stop_gained	Exon 17 of 18	NP_066278.3
	MST1	NM_001393581.1		c.2002G>T	p.Glu668*	stop_gained	Exon 17 of 18	NP_001380510.1
	MST1	NM_001393583.1		c.1876G>T	p.Glu626*	stop_gained	Exon 16 of 17	NP_001380512.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MST1	ENST00000449682.3	TSL:1 MANE Select	c.1966G>T	p.Glu656*	stop_gained	Exon 17 of 18	ENSP00000414287.2	G3XAK1
	MST1	ENST00000448220.5	TSL:5	c.373G>T	p.Glu125*	stop_gained	Exon 4 of 5	ENSP00000394756.1	H7C0F8
	MST1	ENST00000479115.5	TSL:5	n.2021G>T		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460942 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726780

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.3
Vest4		0.96
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=24/176	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs199810403; hg19: chr3-49721797;