rs142371324

Variant names:

• chr17-82088005-C-T
• rs142371324
• NM_004104.5:c.2815G>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.2815G>A​(p.Glu939Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,612,758 control chromosomes in the GnomAD database, including 53 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E939G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (45 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.67
• Publications: 8 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=0.0071086884).
• BP6: Variant 17-82088005-C-T is Benign according to our data. Variant chr17-82088005-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.2815G>A	p.Glu939Lys	missense	Exon 18 of 43	NP_004095.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.2815G>A	p.Glu939Lys	missense	Exon 18 of 43	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.2815G>A	p.Glu939Lys	missense	Exon 18 of 43	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 831 AN: 152166 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00553 AC: 1379 AN: 249508 AF XY: 0.00558

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00467 AC: 6819 AN: 1460472 Hom.: 45 Cov.: 35 AF XY: 0.00463 AC XY: 3365 AN XY: 726530

African (AFR) AF: 0.000866 AC: 29 AN: 33478

American (AMR) AF: 0.00105 AC: 47 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 333 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86256

European-Finnish (FIN) AF: 0.0248 AC: 1292 AN: 52086

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00428 AC: 4759 AN: 1111960

Other (OTH) AF: 0.00469 AC: 283 AN: 60376

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152286 Hom.: 8 Cov.: 33 AF XY: 0.00682 AC XY: 508 AN XY: 74452

African (AFR) AF: 0.000939 AC: 39 AN: 41550

American (AMR) AF: 0.00176 AC: 27 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0331 AC: 352 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00518 AC: 352 AN: 68018

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00466 Hom.: 0

Bravo AF: 0.00288

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00490 AC: 594

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.054
Sift	Benign	0.35	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.46
MVP		0.30
ClinPred		0.012	T
GERP RS		-0.85
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.083
gMVP		0.64
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142371324; hg19: chr17-80045881; COSMIC: COSV100148570; COSMIC: COSV100148570;