chr11-59124465-A-ACT
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2
The NM_198947.4(FAM111B):c.368_369insCT(p.Gln124PhefsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
FAM111B
NM_198947.4 frameshift
NM_198947.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.37
Genes affected
FAM111B (HGNC:24200): (FAM111 trypsin like peptidase B) This gene encodes a protein with a trypsin-like cysteine/serine peptidase domain in the C-terminus. Mutations in this gene are associated with an autosomal dominant form of hereditary fibrosing poikiloderma (HFP). Affected individuals display mottled pigmentation, telangiectasia, epidermal atrophy, tendon contractures, and progressive pulmonary fibrosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. A paralog of this gene which also has a trypsin‐like peptidase domain, FAM111A, is located only 16 kb from this gene on human chromosome 11q12.1. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
BS2
?
High AC in GnomAd at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAM111B | NM_198947.4 | c.368_369insCT | p.Gln124PhefsTer15 | frameshift_variant | 4/4 | ENST00000343597.4 | |
FAM111B | NM_001142703.2 | c.278_279insCT | p.Gln94PhefsTer15 | frameshift_variant | 3/3 | ||
FAM111B | NM_001142704.2 | c.278_279insCT | p.Gln94PhefsTer15 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAM111B | ENST00000343597.4 | c.368_369insCT | p.Gln124PhefsTer15 | frameshift_variant | 4/4 | 1 | NM_198947.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152162Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000639 AC: 16AN: 250336Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135382
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GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461382Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727012
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74352
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Hereditary sclerosing poikiloderma with tendon and pulmonary involvement Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 07, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at