19-1207016-A-T

Variant names:

• chr19-1207016-A-T
• rs587781437
• NM_000455.5:c.103A>T

Variant summary

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

The NM_000455.5(STK11):​c.103A>T​(p.Ile35Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I35V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

STK11 Gene-Disease associations (from GenCC):

• familial pancreatic carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Peutz-Jeghers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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_000455.5. 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
	STK11	NM_000455.5	MANE Select	c.103A>T	p.Ile35Phe	missense	Exon 1 of 10	NP_000446.1
	STK11	NM_001407255.1		c.103A>T	p.Ile35Phe	missense	Exon 1 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1239A>T		non_coding_transcript_exon	Exon 1 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.103A>T	p.Ile35Phe	missense	Exon 1 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.103A>T	p.Ile35Phe	missense	Exon 1 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.-82-11401A>T		intron	N/A	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.61
Sift	Benign	0.086	T
Sift4G	Benign	0.089	T
Polyphen		0.40	B
Vest4		0.60
MutPred		0.43		Loss of MoRF binding (P = 0.1041)
MVP		0.67
MPC		2.6
ClinPred		0.97	D
GERP RS		3.9
PromoterAI		-0.071	Neutral
Varity_R		0.44
gMVP		0.93
Mutation Taster		=34/66	disease causing

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: rs587781437; hg19: chr19-1207015;