rs149982597

Positions:

• chr17-82091278-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004104.5(FASN):​c.1436G>T​(p.Gly479Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,606,734 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (35 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.493

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00413236).
• BP6: Variant 17-82091278-C-A is Benign according to our data. Variant chr17-82091278-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 462002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82091278-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 667 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.1436G>T	p.Gly479Val	missense_variant	9/43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.1436G>T	p.Gly479Val	missense_variant	9/43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.1436G>T	p.Gly479Val	missense_variant	9/43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.1436G>T	p.Gly479Val	missense_variant	9/43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 667 AN: 152256 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00444 AC: 1036 AN: 233350 Hom.: 7 AF XY: 0.00442 AC XY: 566 AN XY: 127938

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00921

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00607 AC: 8823 AN: 1454360 Hom.: 35 Cov.: 34 AF XY: 0.00597 AC XY: 4320 AN XY: 723014

Gnomad4 AFR exome AF: 0.000868

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00147

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00783

Gnomad4 NFE exome AF: 0.00718

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152374 Hom.: 1 Cov.: 33 AF XY: 0.00429 AC XY: 320 AN XY: 74510

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00762

Gnomad4 NFE AF: 0.00723

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00599 Hom.: 1

Bravo AF: 0.00374

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00299 AC: 13

ESP6500EA AF: 0.00724 AC: 62

ExAC AF: 0.00449 AC: 539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	FASN: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

FASN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as likely 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.20
DANN	Benign	0.73
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.4	N;.
REVEL	Benign	0.054
Sift	Benign	0.33	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.0	B;.
Vest4		0.31
MVP		0.13
ClinPred		0.0028	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.083
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149982597; hg19: chr17-80049154;