17-82089086-C-T

Variant names:

• chr17-82089086-C-T
• rs17848930
• NM_004104.5:c.2187G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004104.5(FASN):​c.2187G>A​(p.Thr729Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,578,226 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T729T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (68 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.27
• Publications: 0 publications found

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]

FASN Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-82089086-C-T is Benign according to our data. Variant chr17-82089086-C-T is described in ClinVar as Benign. ClinVar VariationId is 462019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004104.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.2187G>A	p.Thr729Thr	synonymous	Exon 14 of 43	NP_004095.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.2187G>A	p.Thr729Thr	synonymous	Exon 14 of 43	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.2187G>A	p.Thr729Thr	synonymous	Exon 14 of 43	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2529 AN: 152142 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00370 AC: 703 AN: 190224 AF XY: 0.00272

Gnomad AFR exome AF: 0.0566

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00173 AC: 2470 AN: 1425966 Hom.: 68 Cov.: 34 AF XY: 0.00149 AC XY: 1052 AN XY: 706588

African (AFR) AF: 0.0575 AC: 1860 AN: 32330

American (AMR) AF: 0.00318 AC: 126 AN: 39622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00634 AC: 235 AN: 37082

South Asian (SAS) AF: 0.0000732 AC: 6 AN: 81990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49774

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5730

European-Non Finnish (NFE) AF: 0.0000283 AC: 31 AN: 1094914

Other (OTH) AF: 0.00351 AC: 207 AN: 59040

GnomAD4 genome AF: 0.0166 AC: 2534 AN: 152260 Hom.: 71 Cov.: 33 AF XY: 0.0160 AC XY: 1192 AN XY: 74444

African (AFR) AF: 0.0572 AC: 2377 AN: 41548

American (AMR) AF: 0.00751 AC: 115 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67996

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00711 Hom.: 24

Bravo AF: 0.0185

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	FASN-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.13
DANN	Benign	0.77
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs17848930; hg19: chr17-80046962; COSMIC: COSV60750527; COSMIC: COSV60750527;