NM_004104.5:c.3306C>G

Variant names:

• chr17-82087171-G-C
• rs34179714
• NM_004104.5:c.3306C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004104.5(FASN):​c.3306C>G​(p.Ala1102Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,609,482 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (76 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.300
• Publications: 4 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=-0.57).
• BP6: Variant 17-82087171-G-C is Benign according to our data. Variant chr17-82087171-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00653 (9516/1457218) while in subpopulation MID AF = 0.0233 (133/5716). AF 95% confidence interval is 0.0201. There are 76 homozygotes in GnomAdExome4. There are 4822 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.3306C>G	p.Ala1102Ala	synonymous	Exon 21 of 43	NP_004095.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.3306C>G	p.Ala1102Ala	synonymous	Exon 21 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.3333C>G	p.Ala1111Ala	synonymous	Exon 21 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.3330C>G	p.Ala1110Ala	synonymous	Exon 21 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 848 AN: 152146 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00713 AC: 1703 AN: 238752 AF XY: 0.00732

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.00378

Gnomad ASJ exome AF: 0.0458

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.00812

Gnomad OTH exome AF: 0.00935

GnomAD4 exome AF: 0.00653 AC: 9516 AN: 1457218 Hom.: 76 Cov.: 33 AF XY: 0.00665 AC XY: 4822 AN XY: 724646

African (AFR) AF: 0.00176 AC: 59 AN: 33448

American (AMR) AF: 0.00400 AC: 176 AN: 44018

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 1251 AN: 25982

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39588

South Asian (SAS) AF: 0.00442 AC: 379 AN: 85662

European-Finnish (FIN) AF: 0.00416 AC: 215 AN: 51662

Middle Eastern (MID) AF: 0.0233 AC: 133 AN: 5716

European-Non Finnish (NFE) AF: 0.00607 AC: 6748 AN: 1110916

Other (OTH) AF: 0.00918 AC: 553 AN: 60226

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152264 Hom.: 8 Cov.: 33 AF XY: 0.00543 AC XY: 404 AN XY: 74456

African (AFR) AF: 0.00103 AC: 43 AN: 41548

American (AMR) AF: 0.00641 AC: 98 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00682 AC: 464 AN: 68010

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.0111 Hom.: 5

Bravo AF: 0.00585

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.8
DANN	Benign	0.63
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34179714; hg19: chr17-80045047; COSMIC: COSV60754878; COSMIC: COSV60754878;