rs2228305

Positions:

• chr17-82084916-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004104.5(FASN):​c.4447G>A​(p.Val1483Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 1,551,942 control chromosomes in the GnomAD database, including 1,238 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1483L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (191 hom., cov: 34)
  • Exomes 𝑓: 0.034 (1047 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00211218).
• BP6: Variant 17-82084916-C-T is Benign according to our data. Variant chr17-82084916-C-T is described in ClinVar as [Benign]. Clinvar id is 1167210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.4447G>A	p.Val1483Ile	missense_variant	26/43	ENST00000306749.4
FASN	XM_011523538.3	c.4447G>A	p.Val1483Ile	missense_variant	26/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.4447G>A	p.Val1483Ile	missense_variant	26/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.4441G>A	p.Val1481Ile	missense_variant	26/43	5

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6835 AN: 151772 Hom.: 190 Cov.: 34

Gnomad AFR AF: 0.0755

Gnomad AMI AF: 0.0848

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0403

GnomAD3 exomes AF: 0.0415 AC: 6577 AN: 158660 Hom.: 188 AF XY: 0.0429 AC XY: 3605 AN XY: 84108

Gnomad AFR exome AF: 0.0772

Gnomad AMR exome AF: 0.0514

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.00327

Gnomad SAS exome AF: 0.0800

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0384

GnomAD4 exome AF: 0.0339 AC: 47524 AN: 1400048 Hom.: 1047 Cov.: 50 AF XY: 0.0349 AC XY: 24092 AN XY: 690816

Gnomad4 AFR exome AF: 0.0746

Gnomad4 AMR exome AF: 0.0520

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.00159

Gnomad4 SAS exome AF: 0.0802

Gnomad4 FIN exome AF: 0.0247

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0394

GnomAD4 genome AF: 0.0450 AC: 6841 AN: 151894 Hom.: 191 Cov.: 34 AF XY: 0.0439 AC XY: 3263 AN XY: 74266

Gnomad4 AFR AF: 0.0754

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00272

Gnomad4 SAS AF: 0.0870

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0404

Alfa AF: 0.0332 Hom.: 115

Bravo AF: 0.0470

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.0661 AC: 271

ESP6500EA AF: 0.0250 AC: 203

ExAC AF: 0.0251 AC: 2727

Asia WGS AF: 0.0530 AC: 187 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.015
DANN	Benign	0.70
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.040	N;.
REVEL	Benign	0.021
Sift	Benign	0.51	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.012	B;.
Vest4		0.071
ClinPred		0.00043	T
GERP RS		-1.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.065
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228305; hg19: chr17-80042792; COSMIC: COSV60752313; COSMIC: COSV60752313;