17-82095470-GCC-AAT

Position:

• chr17-82095470-GCC-AAT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004104.5(FASN):​c.128_130delGGCinsATT​(p.GlyLeu43AspPhe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FASN NM_004104.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.128_130delGGCinsATT	p.GlyLeu43AspPhe	missense_variant, splice_region_variant		ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.128_130delGGCinsATT	p.GlyLeu43AspPhe	missense_variant, splice_region_variant			XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.128_130delGGCinsATT	p.GlyLeu43AspPhe	missense_variant, splice_region_variant		1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.128_130delGGCinsATT	p.GlyLeu43AspPhe	missense_variant, splice_region_variant		5		ENSP00000488964.1
FASN	ENST00000635197.1	c.128_130delGGCinsATT	p.GlyLeu43AspPhe	missense_variant, splice_region_variant		3		ENSP00000489514.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2020

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with FASN-related disease. This variant is not present in population databases (ExAC no frequency). This variant, c.128_130delGGCinsATT, is a complex sequence change that results in the deletion of 1 amino acid and insertion of 2 amino acids of the FASN protein (p.Gly43_Leu44delinsAspPhe). This variant also falls at the first nucleotide of exon 3 of the FASN coding sequence. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555669729; hg19: chr17-80053346;