chr17-82082588-C-T

Variant names:

• chr17-82082588-C-T
• rs17848946
• NM_004104.5:c.5858G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004104.5(FASN):​c.5858G>A​(p.Arg1953Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,609,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029956013).
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.5858G>A	p.Arg1953Gln	missense_variant	Exon 34 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.5858G>A	p.Arg1953Gln	missense_variant	Exon 34 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.5858G>A	p.Arg1953Gln	missense_variant	Exon 34 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.5852G>A	p.Arg1951Gln	missense_variant	Exon 34 of 43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000172 AC: 42 AN: 244304 Hom.: 0 AF XY: 0.000172 AC XY: 23 AN XY: 133716

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000441

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000904

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000200 AC: 291 AN: 1457596 Hom.: 1 Cov.: 38 AF XY: 0.000188 AC XY: 136 AN XY: 725330

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74502

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Nov 06, 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 glutamine, which is neutral and polar, at codon 1953 of the FASN protein (p.Arg1953Gln). This variant is present in population databases (rs17848946, gnomAD 0.04%). 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: 531048). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.072
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.1
DANN	Benign	0.63
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.80	N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.080
Sift	Benign	0.58	T;.
Sift4G	Benign	0.74	T;T
Polyphen		0.027	B;.
Vest4		0.17
MVP		0.24
ClinPred		0.011	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.19
gMVP		0.53

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: rs17848946; hg19: chr17-80040464;