rs141141382

chr17-82081634-G-Achr17-82081634-G-T

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.6373C>T(p.Arg2125Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,612,650 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. R2125Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.13

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=0.01854816).
• BP6: Variant 17-82081634-G-A is Benign according to our data. Variant chr17-82081634-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 531122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.6373C>T	p.Arg2125Trp	missense_variant	37/43	ENST00000306749.4
FASN	XM_011523538.3	c.6373C>T	p.Arg2125Trp	missense_variant	37/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.6373C>T	p.Arg2125Trp	missense_variant	37/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.6367C>T	p.Arg2123Trp	missense_variant	37/43	5

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000912 AC: 227 AN: 249032 Hom.: 0 AF XY: 0.000908 AC XY: 123 AN XY: 135428

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.00164 AC: 2395 AN: 1460370 Hom.: 4 Cov.: 42 AF XY: 0.00165 AC XY: 1198 AN XY: 726478

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.0000577

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152280 Hom.: 0 Cov.: 31 AF XY: 0.000913 AC XY: 68 AN XY: 74444

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.000876

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.000867 AC: 105

EpiCase AF: 0.00218

EpiControl AF: 0.00148

ClinVar

Significance: 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

Jan 31, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.088
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.063	T;T
Polyphen		0.96	D;.
Vest4		0.40
MVP		0.24
ClinPred		0.46	T
GERP RS		2.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.19
gMVP		0.69

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: rs141141382; hg19: chr17-80039510;