rs534878599

Variant names:

• chr17-82083876-C-T
• rs534878599
• NM_004104.5:c.5114G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-82083876-C-T
• chr17-82083876-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004104.5(FASN):​c.5114G>A​(p.Arg1705Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,572,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R1705W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.92
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12872496).

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.5114G>A	p.Arg1705Gln	missense	Exon 30 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.5114G>A	p.Arg1705Gln	missense	Exon 30 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.5141G>A	p.Arg1714Gln	missense	Exon 30 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.5138G>A	p.Arg1713Gln	missense	Exon 30 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152260 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000991 AC: 18 AN: 181560 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 285 AN: 1419742 Hom.: 1 Cov.: 41 AF XY: 0.000202 AC XY: 142 AN XY: 702010

African (AFR) AF: 0.0000605 AC: 2 AN: 33048

American (AMR) AF: 0.0000535 AC: 2 AN: 37350

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25316

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38242

South Asian (SAS) AF: 0.000481 AC: 39 AN: 81054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.000218 AC: 238 AN: 1090740

Other (OTH) AF: 0.0000339 AC: 2 AN: 58938

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152378 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74512

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000849 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.17
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.033	D
Polyphen		0.58	P
Vest4		0.34
MVP		0.51
ClinPred		0.14	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.63
gMVP		0.70
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs534878599; hg19: chr17-80041752;