17-82082158-A-G

Position:

• chr17-82082158-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004104.5(FASN):​c.6014T>C​(p.Val2005Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00887 in 1,602,730 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2005G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (113 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (253 hom.)
• Consequence: FASN NM_004104.5 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.40

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028517246).
• BP6: Variant 17-82082158-A-G is Benign according to our data. Variant chr17-82082158-A-G is described in ClinVar as [Benign]. Clinvar id is 462088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.6014T>C	p.Val2005Ala	missense_variant, splice_region_variant	36/43	ENST00000306749.4
FASN	XM_011523538.3	c.6014T>C	p.Val2005Ala	missense_variant, splice_region_variant	36/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.6014T>C	p.Val2005Ala	missense_variant, splice_region_variant	36/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.6008T>C	p.Val2003Ala	missense_variant, splice_region_variant	36/43	5

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3680 AN: 152108 Hom.: 108 Cov.: 33

Gnomad AFR AF: 0.0692

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.0240

GnomAD3 exomes AF: 0.0147 AC: 3562 AN: 241562 Hom.: 99 AF XY: 0.0147 AC XY: 1938 AN XY: 131716

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.00777

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.0117

Gnomad SAS exome AF: 0.0460

Gnomad FIN exome AF: 0.0000707

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00725 AC: 10515 AN: 1450506 Hom.: 253 Cov.: 38 AF XY: 0.00800 AC XY: 5778 AN XY: 721876

Gnomad4 AFR exome AF: 0.0730

Gnomad4 AMR exome AF: 0.00890

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.0435

Gnomad4 FIN exome AF: 0.0000237

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0243 AC: 3699 AN: 152224 Hom.: 113 Cov.: 33 AF XY: 0.0244 AC XY: 1813 AN XY: 74426

Gnomad4 AFR AF: 0.0692

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.0133

Gnomad4 SAS AF: 0.0521

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.00717 Hom.: 26

Bravo AF: 0.0262

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0620 AC: 273

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.0157 AC: 1907

Asia WGS AF: 0.0660 AC: 228 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.70	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.069
Sift	Benign	0.80	T;.
Sift4G	Benign	0.81	T;T
Polyphen		0.0050	B;.
Vest4		0.14
ClinPred		0.0011	T
GERP RS		3.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.20
gMVP		0.44

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: rs2228306; hg19: chr17-80040034;