17-82089118-C-T

Position:

• chr17-82089118-C-T

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.2155G>A​(p.Glu719Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00625 in 1,567,442 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (43 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.54

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=0.007240474).
• BP6: Variant 17-82089118-C-T is Benign according to our data. Variant chr17-82089118-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82089118-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 822 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.2155G>A	p.Glu719Lys	missense_variant	14/43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.2155G>A	p.Glu719Lys	missense_variant	14/43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.2155G>A	p.Glu719Lys	missense_variant	14/43	1	NM_004104.5	ENSP00000304592	P1
FASN	ENST00000634990.1	c.2155G>A	p.Glu719Lys	missense_variant	14/43	5		ENSP00000488964

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 822 AN: 152166 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00684

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00579 AC: 1021 AN: 176270 Hom.: 6 AF XY: 0.00573 AC XY: 541 AN XY: 94418

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00433

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00306

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00669

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.00635 AC: 8980 AN: 1415158 Hom.: 43 Cov.: 34 AF XY: 0.00633 AC XY: 4434 AN XY: 700194

Gnomad4 AFR exome AF: 0.00434

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.0000548

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.00159

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.00628

GnomAD4 genome AF: 0.00540 AC: 822 AN: 152284 Hom.: 4 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74472

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00684

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00670 Hom.: 6

Bravo AF: 0.00559

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00209 AC: 9

ESP6500EA AF: 0.00786 AC: 67

ExAC AF: 0.00417 AC: 494

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FASN: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 02, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	0.099
Eigen_PC	Benign	0.059
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.17
Sift	Benign	0.067	T;.
Sift4G	Uncertain	0.060	T;T
Polyphen		1.0	D;.
Vest4		0.46
MVP		0.49
ClinPred		0.026	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs12946178; hg19: chr17-80046994;