rs548430047

chr17-82093411-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004104.5(FASN):c.463A>G(p.Ile155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,600,410 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I155I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.636

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007539779).
• BP6: Variant 17-82093411-T-C is Benign according to our data. Variant chr17-82093411-T-C is described in ClinVar as [Benign]. Clinvar id is 531089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82093411-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000834 (127/152302) while in subpopulation SAS AF= 0.0249 (120/4828). AF 95% confidence interval is 0.0212. There are 2 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.463A>G	p.Ile155Val	missense_variant	5/43	ENST00000306749.4
FASN	XM_011523538.3	c.463A>G	p.Ile155Val	missense_variant	5/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.463A>G	p.Ile155Val	missense_variant	5/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.463A>G	p.Ile155Val	missense_variant	5/43	5

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152184 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00267 AC: 603 AN: 226194 Hom.: 14 AF XY: 0.00349 AC XY: 428 AN XY: 122768

Gnomad AFR exome AF: 0.000142

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0213

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000718

GnomAD4 exome AF: 0.00127 AC: 1837 AN: 1448108 Hom.: 41 Cov.: 36 AF XY: 0.00181 AC XY: 1301 AN XY: 719382

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000467

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74476

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.00275 AC: 330

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FASN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.028
Dann	Benign	0.57
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.11	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.49	N;.
REVEL	Benign	0.025
Sift	Benign	0.26	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.0010	B;.
Vest4		0.035
MVP		0.15
ClinPred		0.0072	T
GERP RS		-4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.096
gMVP		0.84

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: rs548430047; hg19: chr17-80051287; COSMIC: COSV60760066; COSMIC: COSV60760066;