chr17-82090935-C-T

Variant names:

• chr17-82090935-C-T
• rs202040392
• NM_004104.5:c.1627G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004104.5(FASN):​c.1627G>A​(p.Glu543Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000248 in 1,611,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95
• Publications: 5 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08024597).

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.1627G>A	p.Glu543Lys	missense	Exon 10 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.1627G>A	p.Glu543Lys	missense	Exon 10 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.1654G>A	p.Glu552Lys	missense	Exon 10 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.1627G>A	p.Glu543Lys	missense	Exon 10 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000178 AC: 44 AN: 247610 AF XY: 0.000149

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1459684 Hom.: 0 Cov.: 34 AF XY: 0.000242 AC XY: 176 AN XY: 726052

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.000224 AC: 10 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52152

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000291 AC: 324 AN: 1111634

Other (OTH) AF: 0.000298 AC: 18 AN: 60342

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74378

African (AFR) AF: 0.000169 AC: 7 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.000491

EpiControl AF: 0.000298

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.052
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.024	D
Sift4G	Benign	0.061	T
Polyphen		0.56	P
Vest4		0.51
MVP		0.42
ClinPred		0.088	T
GERP RS		5.2
Varity_R		0.66
gMVP		0.47
Mutation Taster		=88/12	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: rs202040392; hg19: chr17-80048811; COSMIC: COSV60753675; COSMIC: COSV60753675;