rs4246444

Positions:

• chr17-82081076-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004104.5(FASN):​c.6595+88A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,475,934 control chromosomes in the GnomAD database, including 390,728 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.74 (42169 hom., cov: 34)
  • Exomes 𝑓: 0.72 (348559 hom.)
• Consequence: FASN NM_004104.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.204

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.6595+88A>C		intron_variant		ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.6595+88A>C		intron_variant			XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.6595+88A>C		intron_variant		1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.6589+88A>C		intron_variant		5		ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112502 AN: 152022 Hom.: 42120 Cov.: 34

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.734

GnomAD4 exome AF: 0.722 AC: 955637 AN: 1323794 Hom.: 348559 Cov.: 22 AF XY: 0.715 AC XY: 469355 AN XY: 656122

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.736

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.566

Gnomad4 FIN exome AF: 0.755

Gnomad4 NFE exome AF: 0.744

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.740 AC: 112607 AN: 152140 Hom.: 42169 Cov.: 34 AF XY: 0.736 AC XY: 54721 AN XY: 74390

Gnomad4 AFR AF: 0.794

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.750

Gnomad4 NFE AF: 0.745

Gnomad4 OTH AF: 0.735

Alfa AF: 0.735 Hom.: 59139

Bravo AF: 0.744

Asia WGS AF: 0.568 AC: 1977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs4246444; hg19: chr17-80038952; COSMIC: COSV60755765; COSMIC: COSV60755765;