rs149982597

Variant names:

• chr17-82091278-C-A
• rs149982597
• NM_004104.5:c.1436G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-82091278-C-A
• chr17-82091278-C-T

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.1436G>T​(p.Gly479Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,606,734 control chromosomes in the GnomAD database, including 36 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (35 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.493
• Publications: 4 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=0.00413236).
• BP6: Variant 17-82091278-C-A is Benign according to our data. Variant chr17-82091278-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 35 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.1436G>T	p.Gly479Val	missense	Exon 9 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.1436G>T	p.Gly479Val	missense	Exon 9 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.1463G>T	p.Gly488Val	missense	Exon 9 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.1436G>T	p.Gly479Val	missense	Exon 9 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 667 AN: 152256 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00444 AC: 1036 AN: 233350 AF XY: 0.00442

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00921

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00607 AC: 8823 AN: 1454360 Hom.: 35 Cov.: 34 AF XY: 0.00597 AC XY: 4320 AN XY: 723014

African (AFR) AF: 0.000868 AC: 29 AN: 33414

American (AMR) AF: 0.00142 AC: 63 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 38 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85708

European-Finnish (FIN) AF: 0.00783 AC: 394 AN: 50336

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.00718 AC: 7965 AN: 1109282

Other (OTH) AF: 0.00551 AC: 331 AN: 60044

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152374 Hom.: 1 Cov.: 33 AF XY: 0.00429 AC XY: 320 AN XY: 74510

African (AFR) AF: 0.00144 AC: 60 AN: 41578

American (AMR) AF: 0.00137 AC: 21 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00762 AC: 81 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00599 Hom.: 10

Bravo AF: 0.00374

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00299 AC: 13

ESP6500EA AF: 0.00724 AC: 62

ExAC AF: 0.00449 AC: 539

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epileptic encephalopathy (1)
-	-	1	FASN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.20
DANN	Benign	0.73
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.49
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.054
Sift	Benign	0.33	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.31
MVP		0.13
ClinPred		0.0028	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.083
gMVP		0.44
Mutation Taster		=92/8	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: rs149982597; hg19: chr17-80049154; COSMIC: COSV106099692; COSMIC: COSV106099692;