rs150748779

Variant names:

• chr17-82082054-C-A
• rs150748779
• NM_004104.5:c.6118G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-82082054-C-A
• chr17-82082054-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.6118G>T​(p.Ala2040Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 1,610,508 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2040T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.450
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011911303).
• BP6: Variant 17-82082054-C-A is Benign according to our data. Variant chr17-82082054-C-A is described in ClinVar as Benign. ClinVar VariationId is 462090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.6118G>T	p.Ala2040Ser	missense	Exon 36 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.6118G>T	p.Ala2040Ser	missense	Exon 36 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.6145G>T	p.Ala2049Ser	missense	Exon 36 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.6142G>T	p.Ala2048Ser	missense	Exon 36 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000504 AC: 125 AN: 248044 AF XY: 0.000467

Gnomad AFR exome AF: 0.00682

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1458254 Hom.: 1 Cov.: 38 AF XY: 0.000186 AC XY: 135 AN XY: 725520

African (AFR) AF: 0.00789 AC: 264 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111954

Other (OTH) AF: 0.000414 AC: 25 AN: 60356

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74454

African (AFR) AF: 0.00790 AC: 328 AN: 41538

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67996

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000509 Hom.: 0

Bravo AF: 0.00239

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000668 AC: 81

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.0080
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.067
Sift	Uncertain	0.023	D
Sift4G	Benign	0.20	T
Polyphen		0.093	B
Vest4		0.16
MVP		0.35
ClinPred		0.012	T
GERP RS		0.49
Varity_R		0.36
gMVP		0.26
Mutation Taster		=96/4	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: rs150748779; hg19: chr17-80039930; COSMIC: COSV100147839; COSMIC: COSV100147839;