17-82085863-A-G

Variant names:

• chr17-82085863-A-G
• rs2229422
• NM_004104.5:c.3741T>C

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.3741T>C​(p.Ala1247Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,538,636 control chromosomes in the GnomAD database, including 78,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6709 hom., cov: 33)
  • Exomes 𝑓: 0.32 (71500 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.426
• Publications: 24 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=-0.81).
• BP6: Variant 17-82085863-A-G is Benign according to our data. Variant chr17-82085863-A-G is described in ClinVar as Benign. ClinVar VariationId is 1170033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.3741T>C	p.Ala1247Ala	synonymous_variant	Exon 23 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.3741T>C	p.Ala1247Ala	synonymous_variant	Exon 23 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.3741T>C	p.Ala1247Ala	synonymous_variant	Exon 23 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.3735T>C	p.Ala1245Ala	synonymous_variant	Exon 23 of 43	5		ENSP00000488964.1
FASN	ENST00000579410.1	n.-203T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43837 AN: 152008 Hom.: 6705 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.252 AC: 38188 AN: 151766 AF XY: 0.251

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.316 AC: 437494 AN: 1386510 Hom.: 71500 Cov.: 53 AF XY: 0.311 AC XY: 212843 AN XY: 683750

African (AFR) AF: 0.220 AC: 7102 AN: 32230

American (AMR) AF: 0.155 AC: 5812 AN: 37470

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 4914 AN: 24568

East Asian (EAS) AF: 0.283 AC: 10458 AN: 36910

South Asian (SAS) AF: 0.184 AC: 14503 AN: 78968

European-Finnish (FIN) AF: 0.356 AC: 12269 AN: 34474

Middle Eastern (MID) AF: 0.206 AC: 1080 AN: 5252

European-Non Finnish (NFE) AF: 0.338 AC: 364639 AN: 1078918

Other (OTH) AF: 0.290 AC: 16717 AN: 57720

GnomAD4 genome AF: 0.288 AC: 43848 AN: 152126 Hom.: 6709 Cov.: 33 AF XY: 0.289 AC XY: 21512 AN XY: 74370

African (AFR) AF: 0.228 AC: 9451 AN: 41528

American (AMR) AF: 0.228 AC: 3488 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 702 AN: 3472

East Asian (EAS) AF: 0.294 AC: 1520 AN: 5170

South Asian (SAS) AF: 0.183 AC: 885 AN: 4824

European-Finnish (FIN) AF: 0.363 AC: 3848 AN: 10602

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22926 AN: 67936

Other (OTH) AF: 0.287 AC: 604 AN: 2104

Alfa AF: 0.299 Hom.: 3322

Bravo AF: 0.276

Asia WGS AF: 0.197 AC: 685 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.39
DANN	Benign	0.35
PhyloP100		-0.43
Mutation Taster		=96/4	polymorphism (auto)

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: rs2229422; hg19: chr17-80043739; COSMIC: COSV60755892; COSMIC: COSV60755892;