NM_004104.5:c.4996C>T

Variant names:

• chr17-82084077-G-A
• rs377037839
• NM_004104.5:c.4996C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004104.5(FASN):​c.4996C>T​(p.Arg1666Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,554,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16843131).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.4996C>T	p.Arg1666Cys	missense_variant	Exon 29 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.4996C>T	p.Arg1666Cys	missense_variant	Exon 29 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.4996C>T	p.Arg1666Cys	missense_variant	Exon 29 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.4990C>T	p.Arg1664Cys	missense_variant	Exon 29 of 43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000150 AC: 23 AN: 153010 Hom.: 0 AF XY: 0.000133 AC XY: 11 AN XY: 82722

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.0000793

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000897

Gnomad SAS exome AF: 0.000729

Gnomad FIN exome AF: 0.0000723

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000528 AC: 74 AN: 1402650 Hom.: 0 Cov.: 42 AF XY: 0.0000621 AC XY: 43 AN XY: 692786

Gnomad4 AFR exome AF: 0.000157

Gnomad4 AMR exome AF: 0.0000550

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000554

Gnomad4 SAS exome AF: 0.000701

Gnomad4 FIN exome AF: 0.0000217

Gnomad4 NFE exome AF: 0.00000462

Gnomad4 OTH exome AF: 0.0000515

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000888 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1666 of the FASN protein (p.Arg1666Cys). This variant is present in population databases (rs377037839, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FASN-related conditions. ClinVar contains an entry for this variant (Variation ID: 531054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.5	D;.
REVEL	Benign	0.086
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.49
MVP		0.44
ClinPred		0.14	T
GERP RS		2.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.23
gMVP		0.71

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: rs377037839; hg19: chr17-80041953;