17-82084716-T-TCTA
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The NM_004104.5(FASN):c.4565-1_4565insTAG(p.Glu1521_Asp1522insVal) variant causes a inframe insertion, splice region change. The variant allele was found at a frequency of 0.000199 in 1,558,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
FASN
NM_004104.5 inframe_insertion, splice_region
NM_004104.5 inframe_insertion, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.83
Genes affected
FASN (HGNC:3594): (fatty acid synthase) The enzyme encoded by this gene is a multifunctional protein. Its main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids. In some cancer cell lines, this protein has been found to be fused with estrogen receptor-alpha (ER-alpha), in which the N-terminus of FAS is fused in-frame with the C-terminus of ER-alpha. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_004104.5. Strenght limited to Supporting due to length of the change: 1aa.
BS2
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FASN | NM_004104.5 | c.4565-1_4565insTAG | p.Glu1521_Asp1522insVal | inframe_insertion, splice_region_variant | ENST00000306749.4 | ||
FASN | XM_011523538.3 | c.4565-1_4565insTAG | p.Glu1521_Asp1522insVal | inframe_insertion, splice_region_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FASN | ENST00000306749.4 | c.4565-1_4565insTAG | p.Glu1521_Asp1522insVal | inframe_insertion, splice_region_variant | 1 | NM_004104.5 | P1 | ||
FASN | ENST00000634990.1 | c.4559-1_4559insTAG | p.Glu1519_Asp1520insVal | inframe_insertion, splice_region_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152118Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000145 AC: 24AN: 165408Hom.: 0 AF XY: 0.000181 AC XY: 16AN XY: 88172
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GnomAD4 exome AF: 0.000210 AC: 296AN: 1406864Hom.: 0 Cov.: 44 AF XY: 0.000219 AC XY: 152AN XY: 694714
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GnomAD4 genome AF: 0.0000920 AC: 14AN: 152118Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This variant, c.4565-3_4565-1dup, duplicates 3 nucleotides in intron 26 of the FASN mRNA, including the canonical splice site. It is expected to either insert 1 amino acid to the FASN protein (p.Glu1521_Asp1522insVal) or to have no protein effect. This variant is present in population databases (rs764277201, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FASN-related conditions. ClinVar contains an entry for this variant (Variation ID: 462057). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at