chr17-82082574-C-T

Variant names:

• chr17-82082574-C-T
• rs145688025
• NM_004104.5:c.5872G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004104.5(FASN):​c.5872G>A​(p.Glu1958Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,609,570 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.84
• Publications: 12 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01355502).
• BP6: Variant 17-82082574-C-T is Benign according to our data. Variant chr17-82082574-C-T is described in ClinVar as Benign. ClinVar VariationId is 462083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.5872G>A	p.Glu1958Lys	missense	Exon 34 of 43	NP_004095.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.5872G>A	p.Glu1958Lys	missense	Exon 34 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.5899G>A	p.Glu1967Lys	missense	Exon 34 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.5896G>A	p.Glu1966Lys	missense	Exon 34 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 675 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00376 AC: 917 AN: 243830 AF XY: 0.00372

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00954

Gnomad NFE exome AF: 0.00566

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00610 AC: 8882 AN: 1457210 Hom.: 32 Cov.: 38 AF XY: 0.00580 AC XY: 4209 AN XY: 725184

African (AFR) AF: 0.00140 AC: 47 AN: 33472

American (AMR) AF: 0.00163 AC: 73 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86242

European-Finnish (FIN) AF: 0.00815 AC: 400 AN: 49070

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00713 AC: 7929 AN: 1111828

Other (OTH) AF: 0.00550 AC: 332 AN: 60350

GnomAD4 genome AF: 0.00442 AC: 674 AN: 152360 Hom.: 5 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74500

African (AFR) AF: 0.00151 AC: 63 AN: 41586

American (AMR) AF: 0.000980 AC: 15 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00695 AC: 473 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00426 Hom.: 7

Bravo AF: 0.00370

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00583 AC: 50

ExAC AF: 0.00346 AC: 417

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00575

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.72
MVP		0.47
ClinPred		0.016	T
GERP RS		4.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Varity_R		0.67
gMVP		0.79
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs145688025; hg19: chr17-80040450; COSMIC: COSV60751510; COSMIC: COSV60751510;