rs149224679

chr17-82079377-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004104.5(FASN):c.7378G>A(p.Ala2460Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,612,946 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2460A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040204644).
• BP6: Variant 17-82079377-C-T is Benign according to our data. Variant chr17-82079377-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 462110.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.7378G>A	p.Ala2460Thr	missense_variant	42/43	ENST00000306749.4
FASN	XM_011523538.3	c.7378G>A	p.Ala2460Thr	missense_variant	42/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.7378G>A	p.Ala2460Thr	missense_variant	42/43	1	NM_004104.5	P1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000353 AC: 88 AN: 249638 Hom.: 0 AF XY: 0.000384 AC XY: 52 AN XY: 135572

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000596

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000571 AC: 834 AN: 1460574 Hom.: 1 Cov.: 37 AF XY: 0.000568 AC XY: 413 AN XY: 726594

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000306

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74510

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000583 Hom.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000347 AC: 42

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.7378G>A (p.A2460T) alteration is located in exon 42 (coding exon 41) of the FASN gene. This alteration results from a G to A substitution at nucleotide position 7378, causing the alanine (A) at amino acid position 2460 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	21
Dann	Benign	0.87
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.75	N;.
REVEL	Benign	0.058
Sift	Benign	0.53	T;.
Sift4G	Benign	0.55	T;T
Polyphen		0.51	P;.
Vest4		0.38
MVP		0.46
ClinPred		0.0055	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs149224679; hg19: chr17-80037253; COSMIC: COSV104405063;