rs201899557
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000455.5(STK11):c.735-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,611,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000455.5 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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STK11 | NM_000455.5 | c.735-9G>A | intron_variant | Intron 5 of 9 | ENST00000326873.12 | NP_000446.1 | ||
STK11 | NM_001407255.1 | c.735-9G>A | intron_variant | Intron 5 of 8 | NP_001394184.1 | |||
STK11 | NR_176325.1 | n.2002-9G>A | intron_variant | Intron 6 of 10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.735-9G>A | intron_variant | Intron 5 of 9 | 1 | NM_000455.5 | ENSP00000324856.6 | |||
STK11 | ENST00000652231.1 | c.735-9G>A | intron_variant | Intron 5 of 8 | ENSP00000498804.1 | |||||
STK11 | ENST00000585748.3 | c.363-9G>A | intron_variant | Intron 7 of 11 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000929 AC: 23AN: 247564Hom.: 0 AF XY: 0.0000890 AC XY: 12AN XY: 134840
GnomAD4 exome AF: 0.0000384 AC: 56AN: 1459116Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 725682
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74434
ClinVar
Submissions by phenotype
not specified Benign:3
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Variant summary: STK11 c.735-9G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 247564 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 78-fold the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.735-9G>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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Hereditary cancer-predisposing syndrome Benign:3
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Peutz-Jeghers syndrome Benign:3
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not provided Benign:2
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The STK11 c.735-9G>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University, and in the Insight Hereditary Tumors databases. The variant was not identified in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs201899557) as with likely benign allele and in the ClinVar and Clinvitae databases as likely benign by Invitae and Color Genomics. The variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002). The variant was identified in control databases in 23 of 245260 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5454 chromosomes (freq: 0.0002), Latino in 17 of 33522 chromosomes (freq: 0.0005), European Non-Finnish in 4 of 111066 chromosomes (freq: 0.00004), East Asian in 1 of 17230 chromosomes (freq: 0.00006), while the variant was not observed in the African, Ashkenazi Jewish, European Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at