Genetic Variant FASN:p.Ala1247Ala (chr17-82085863-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.426

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 link	c.3741T>C	p.Ala1247Ala	synonymous_variant	Exon 23 of 43	ENST00000306749.4	NP_004095.4	P49327
FASN	XM_011523538.3 link	c.3741T>C	p.Ala1247Ala	synonymous_variant	Exon 23 of 43		XP_011521840.1	P49327

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FASN	ENST00000306749.4 link	c.3741T>C	p.Ala1247Ala	synonymous_variant	Exon 23 of 43	1	NM_004104.5	ENSP00000304592.2	P49327
FASN	ENST00000634990.1 link	c.3735T>C	p.Ala1245Ala	synonymous_variant	Exon 23 of 43	5		ENSP00000488964.1	A0A0U1RQF0
FASN	ENST00000579410.1 link	n.-203T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43837

AN:

152008

Hom.:

6705

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.252

AC:

38188

AN:

151766

Hom.:

5228

AF XY:

0.251

AC XY:

20753

AN XY:

82588

show subpopulations

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 SAS exome

AF:

0.177

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.:

AF XY:

0.311

AC XY:

212843

AN XY:

683750

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.155

Gnomad4 ASJ exome

AF:

0.200

Gnomad4 EAS exome

AF:

0.283

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.356

Gnomad4 NFE exome

AF:

0.338

Gnomad4 OTH exome

AF:

0.290

GnomAD4 genome

AF:

0.288

AC:

43848

AN:

152126

Hom.:

6709

Cov.:

AF XY:

0.289

AC XY:

21512

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.228

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.202

Gnomad4 EAS

AF:

0.294

Gnomad4 SAS

AF:

0.183

Gnomad4 FIN

AF:

0.363

Gnomad4 NFE

AF:

0.337

Gnomad4 OTH

AF:

0.287

Alfa

AF:

0.306

Hom.:

2073

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

LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over