chr11-130159982-G-A

Variant names:

• chr11-130159982-G-A
• rs137852932
• NM_021978.4:c.3G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_021978.4(ST14):​c.3G>A​(p.Met1?) variant causes a start lost change. 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ST14 NM_021978.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.62
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 94 codons. Genomic position: 130188568. Lost 0.109 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-130159982-G-A is Pathogenic according to our data. Variant chr11-130159982-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4039.Status of the report is no_assertion_criteria_provided, 0 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.3G>A	p.Met1?	start_lost	Exon 1 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.3G>A	p.Met1?	start_lost	Exon 1 of 19	ENSP00000278742.5	Q9Y5Y6
	ST14	ENST00000894129.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 19	ENSP00000564188.1
	ST14	ENST00000894128.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 19	ENSP00000564187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1243402 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 608666

African (AFR) AF: 0.00 AC: 0 AN: 25266

American (AMR) AF: 0.00 AC: 0 AN: 19708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20252

East Asian (EAS) AF: 0.00 AC: 0 AN: 26926

South Asian (SAS) AF: 0.00 AC: 0 AN: 58120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3976

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 996020

Other (OTH) AF: 0.00 AC: 0 AN: 49708

GnomAD4 genome Cov.: 32

Alfa AF: 0.000580 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive congenital ichthyosis 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.094	T
PhyloP100		3.6
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.38	B
Vest4		0.71
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0372)
MVP		0.98
ClinPred		0.82	D
GERP RS		3.1
PromoterAI		-0.11	Neutral
Varity_R		0.92
gMVP		0.29
Mutation Taster		=12/188	disease causing (ClinVar)

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: rs137852932; hg19: chr11-130029877;