chr11-130188270-C-T

Variant names:

• chr11-130188270-C-T
• rs1953258238
• NM_021978.4:c.238C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_021978.4(ST14):​c.238C>T​(p.Gln80*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ST14 NM_021978.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

Genes affected

ST14 (HGNC:11344): (ST14 transmembrane serine protease matriptase) The protein encoded by this gene is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scattering factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis. [provided by RefSeq, Jul 2008]

ST14 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 11

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-130188270-C-T is Pathogenic according to our data. Variant chr11-130188270-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 872044.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021978.4. 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
	ST14	NM_021978.4	MANE Select	c.238C>T	p.Gln80*	stop_gained	Exon 2 of 19	NP_068813.1	Q9Y5Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST14	ENST00000278742.6	TSL:1 MANE Select	c.238C>T	p.Gln80*	stop_gained	Exon 2 of 19	ENSP00000278742.5	Q9Y5Y6
	ST14	ENST00000894129.1		c.238C>T	p.Gln80*	stop_gained	Exon 2 of 19	ENSP00000564188.1
	ST14	ENST00000894128.1		c.238C>T	p.Gln80*	stop_gained	Exon 2 of 19	ENSP00000564187.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.63	D
PhyloP100		1.2
Vest4		0.91
GERP RS		3.9
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1953258238; hg19: chr11-130058165; COSMIC: COSV99598942; COSMIC: COSV99598942;