17-82081229-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004104.5(FASN):c.6530G>A(p.Arg2177His) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,591,400 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R2177R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.10

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026693195).
• BP6: Variant 17-82081229-C-T is Benign according to our data. Variant chr17-82081229-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 462101.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.6530G>A	p.Arg2177His	missense_variant	38/43	ENST00000306749.4
FASN	XM_011523538.3	c.6530G>A	p.Arg2177His	missense_variant	38/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.6530G>A	p.Arg2177His	missense_variant	38/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.6524G>A	p.Arg2175His	missense_variant	38/43	5

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000157 AC: 33 AN: 210654 Hom.: 0 AF XY: 0.000123 AC XY: 14 AN XY: 114042

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000113

Gnomad FIN exome AF: 0.0000583

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000702 AC: 101 AN: 1439068 Hom.: 0 Cov.: 36 AF XY: 0.0000686 AC XY: 49 AN XY: 713766

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.000241

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000108

Gnomad4 FIN exome AF: 0.0000605

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.0000503

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74486

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000518

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000125 AC: 15

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.26
Sift	Uncertain	0.012	D;.
Sift4G	Benign	0.093	T;T
Polyphen		0.98	D;.
Vest4		0.31
MVP		0.59
ClinPred		0.058	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs9890362; hg19: chr17-80039105; COSMIC: COSV100148010; COSMIC: COSV100148010;