rs764277201

Variant names:

• chr17-82084716-T-TCTA
• rs764277201
• NM_004104.5:c.4565-3_4565-1dupTAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_004104.5(FASN):​c.4565-3_4565-1dupTAG variant causes a splice acceptor, intron 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 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.83
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027070064 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 0 (no position change), new splice context is: cctccctgtttccctagtAGaca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.4565-3_4565-1dupTAG		splice_acceptor intron	N/A	NP_004095.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.4565-1_4565insTAG		splice_acceptor intron	N/A	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.4559-1_4559insTAG		splice_acceptor intron	N/A	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152118 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000145 AC: 24 AN: 165408 AF XY: 0.000181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000210 AC: 296 AN: 1406864 Hom.: 0 Cov.: 44 AF XY: 0.000219 AC XY: 152 AN XY: 694714

African (AFR) AF: 0.0000312 AC: 1 AN: 32098

American (AMR) AF: 0.000191 AC: 7 AN: 36668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.00 AC: 0 AN: 36432

South Asian (SAS) AF: 0.0000996 AC: 8 AN: 80282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48340

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5704

European-Non Finnish (NFE) AF: 0.000245 AC: 265 AN: 1083790

Other (OTH) AF: 0.000154 AC: 9 AN: 58292

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152118 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68016

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000140

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epileptic encephalopathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=23/77	disease causing

Splicing

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

Other links and lift over

dbSNP: rs764277201; hg19: chr17-80042592;