rs45507397

chr17-82081205-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004104.5(FASN):c.6554G>A(p.Arg2185Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,594,278 control chromosomes in the GnomAD database, including 28 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R2185W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (16 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048415065).
• BP6: Variant 17-82081205-C-T is Benign according to our data. Variant chr17-82081205-C-T is described in ClinVar as [Benign]. Clinvar id is 462102.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-82081205-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00786 (1197/152334) while in subpopulation AFR AF= 0.0273 (1137/41580). AF 95% confidence interval is 0.026. There are 12 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.6554G>A	p.Arg2185Gln	missense_variant	38/43	ENST00000306749.4
FASN	XM_011523538.3	c.6554G>A	p.Arg2185Gln	missense_variant	38/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.6554G>A	p.Arg2185Gln	missense_variant	38/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.6548G>A	p.Arg2183Gln	missense_variant	38/43	5

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1199 AN: 152216 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00198 AC: 427 AN: 215524 Hom.: 2 AF XY: 0.00138 AC XY: 162 AN XY: 116976

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000314

Gnomad OTH exome AF: 0.000367

GnomAD4 exome AF: 0.000874 AC: 1260 AN: 1441944 Hom.: 16 Cov.: 36 AF XY: 0.000727 AC XY: 520 AN XY: 715558

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000204

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000263

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.00786 AC: 1197 AN: 152334 Hom.: 12 Cov.: 33 AF XY: 0.00759 AC XY: 565 AN XY: 74488

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00211 Hom.: 3

Bravo AF: 0.00934

ESP6500AA AF: 0.0290 AC: 127

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00220 AC: 264

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.80	N;.
REVEL	Benign	0.081
Sift	Benign	0.25	T;.
Sift4G	Benign	0.33	T;T
Polyphen		0.10	B;.
Vest4		0.17
MVP		0.36
ClinPred		0.011	T
GERP RS		-1.4
Varity_R		0.080
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs45507397; hg19: chr17-80039081;