rs150915750

chr17-82085630-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004104.5(FASN):c.3974C>T(p.Pro1325Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,596,154 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1325P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.50

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010358661).
• BP6: Variant 17-82085630-G-A is Benign according to our data. Variant chr17-82085630-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82085630-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.3974C>T	p.Pro1325Leu	missense_variant	23/43	ENST00000306749.4
FASN	XM_011523538.3	c.3974C>T	p.Pro1325Leu	missense_variant	23/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.3974C>T	p.Pro1325Leu	missense_variant	23/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.3968C>T	p.Pro1323Leu	missense_variant	23/43	5
FASN	ENST00000579410.1	n.31C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00151 AC: 325 AN: 215482 Hom.: 1 AF XY: 0.00165 AC XY: 194 AN XY: 117496

Gnomad AFR exome AF: 0.000476

Gnomad AMR exome AF: 0.000284

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00350

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00178 AC: 2565 AN: 1443866 Hom.: 9 Cov.: 68 AF XY: 0.00177 AC XY: 1270 AN XY: 716920

Gnomad4 AFR exome AF: 0.000424

Gnomad4 AMR exome AF: 0.000446

Gnomad4 ASJ exome AF: 0.0000775

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74468

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00329

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00177 Hom.: 1

Bravo AF: 0.00106

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000934 AC: 8

ExAC AF: 0.00114 AC: 136

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FASN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.078
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.17
Sift	Benign	0.077	T;.
Sift4G	Benign	0.25	T;T
Polyphen		0.87	P;.
Vest4		0.58
MVP		0.35
ClinPred		0.036	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.80

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: rs150915750; hg19: chr17-80043506;