17-82092928-G-A

Variant names:

• chr17-82092928-G-A
• rs115212667
• NM_004104.5:c.747C>T

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.747C>T​(p.Ala249Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,606,862 control chromosomes in the GnomAD database, including 20 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. A249A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (14 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.55
• Publications: 1 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=-0.76).
• BP6: Variant 17-82092928-G-A is Benign according to our data. Variant chr17-82092928-G-A is described in ClinVar as Benign. ClinVar VariationId is 462113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00633 (964/152312) while in subpopulation AFR AF = 0.022 (916/41560). AF 95% confidence interval is 0.0209. There are 6 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.747C>T	p.Ala249Ala	synonymous	Exon 6 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.747C>T	p.Ala249Ala	synonymous	Exon 6 of 43	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.747C>T	p.Ala249Ala	synonymous	Exon 6 of 43	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 964 AN: 152194 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00170 AC: 401 AN: 235390 AF XY: 0.00132

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.0000566

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000474

Gnomad OTH exome AF: 0.000695

GnomAD4 exome AF: 0.000748 AC: 1088 AN: 1454550 Hom.: 14 Cov.: 36 AF XY: 0.000645 AC XY: 466 AN XY: 722908

African (AFR) AF: 0.0259 AC: 865 AN: 33408

American (AMR) AF: 0.00123 AC: 54 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25860

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39466

South Asian (SAS) AF: 0.000294 AC: 25 AN: 85174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51426

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5738

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1109436

Other (OTH) AF: 0.00175 AC: 105 AN: 60072

GnomAD4 genome AF: 0.00633 AC: 964 AN: 152312 Hom.: 6 Cov.: 33 AF XY: 0.00643 AC XY: 479 AN XY: 74478

African (AFR) AF: 0.0220 AC: 916 AN: 41560

American (AMR) AF: 0.00229 AC: 35 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00246 Hom.: 3

Bravo AF: 0.00709

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Feb 03, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.34
DANN	Benign	0.75
PhyloP100		-5.6
Mutation Taster		=68/32	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: rs115212667; hg19: chr17-80050804;