NM_004104.5:c.2155G>A

Variant names:

• chr17-82089118-C-T
• rs12946178
• NM_004104.5:c.2155G>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.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
• Publications: 9 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=0.007240474).
• BP6: Variant 17-82089118-C-T is Benign according to our data. Variant chr17-82089118-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 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.2155G>A	p.Glu719Lys	missense	Exon 14 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.2155G>A	p.Glu719Lys	missense	Exon 14 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.2182G>A	p.Glu728Lys	missense	Exon 14 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.2179G>A	p.Glu727Lys	missense	Exon 14 of 43	ENSP00000610405.1

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

GnomAD2 exomes AF: 0.00579 AC: 1021 AN: 176270 AF XY: 0.00573

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 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

African (AFR) AF: 0.00434 AC: 139 AN: 32016

American (AMR) AF: 0.00414 AC: 157 AN: 37904

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 703 AN: 25374

East Asian (EAS) AF: 0.0000548 AC: 2 AN: 36484

South Asian (SAS) AF: 0.00313 AC: 255 AN: 81368

European-Finnish (FIN) AF: 0.00159 AC: 78 AN: 49056

Middle Eastern (MID) AF: 0.00297 AC: 17 AN: 5722

European-Non Finnish (NFE) AF: 0.00667 AC: 7261 AN: 1088612

Other (OTH) AF: 0.00628 AC: 368 AN: 58622

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

African (AFR) AF: 0.00419 AC: 174 AN: 41558

American (AMR) AF: 0.00359 AC: 55 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00684 AC: 465 AN: 68006

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00638 Hom.: 12

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Benign	0.067	T
Sift4G	Uncertain	0.060	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
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs12946178; hg19: chr17-80046994;