rs139276176

Variant names:

• chr17-82085558-C-T
• rs139276176
• NM_004104.5:c.4046G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-82085558-C-T
• chr17-82085558-C-A
• chr17-82085558-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004104.5(FASN):​c.4046G>A​(p.Arg1349Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,595,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1349W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.258
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030251443).

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.4046G>A	p.Arg1349Gln	missense	Exon 23 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.4046G>A	p.Arg1349Gln	missense	Exon 23 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.4073G>A	p.Arg1358Gln	missense	Exon 23 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.4070G>A	p.Arg1357Gln	missense	Exon 23 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000885 AC: 19 AN: 214596 AF XY: 0.0000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 265 AN: 1442906 Hom.: 0 Cov.: 66 AF XY: 0.000173 AC XY: 124 AN XY: 716164

African (AFR) AF: 0.0000302 AC: 1 AN: 33110

American (AMR) AF: 0.000118 AC: 5 AN: 42288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25720

East Asian (EAS) AF: 0.00 AC: 0 AN: 38698

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000219 AC: 242 AN: 1103628

Other (OTH) AF: 0.000268 AC: 16 AN: 59626

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.0000750 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.8
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.26
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.0030
Sift	Benign	0.36	T
Sift4G	Benign	0.55	T
Polyphen		0.13	B
Vest4		0.16
MVP		0.29
ClinPred		0.057	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.065
gMVP		0.58
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs139276176; hg19: chr17-80043434; COSMIC: COSV60756048; COSMIC: COSV60756048;