17-82093220-C-A

Variant names:

• chr17-82093220-C-A
• NM_004104.5:c.654G>T
• FASN p.Ala218Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004104.5(FASN):​c.654G>T​(p.Ala218Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A218A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FASN NM_004104.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001250
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.275
• Publications: 0 publications found

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]

FASN Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP7: Synonymous conserved (PhyloP=-0.275 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004104.5. 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
	FASN	NM_004104.5	MANE Select	c.654G>T	p.Ala218Ala	splice_region synonymous	Exon 5 of 43	NP_004095.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.654G>T	p.Ala218Ala	splice_region synonymous	Exon 5 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.681G>T	p.Ala227Ala	splice_region synonymous	Exon 5 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.654G>T	p.Ala218Ala	splice_region synonymous	Exon 5 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424794 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 705514

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 39358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 37988

South Asian (SAS) AF: 0.00 AC: 0 AN: 81552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094376

Other (OTH) AF: 0.00 AC: 0 AN: 58992

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0070
DANN	Benign	0.79
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0060
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-80051096;