chr17-82084064-G-A

Variant names:

• chr17-82084064-G-A
• rs753648795
• NM_004104.5:c.5009C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004104.5(FASN):​c.5009C>T​(p.Thr1670Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,549,438 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T1670T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000035 (1 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.5009C>T	p.Thr1670Met	missense	Exon 29 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.5009C>T	p.Thr1670Met	missense	Exon 29 of 43	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.5003C>T	p.Thr1668Met	missense	Exon 29 of 43	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000958 AC: 14 AN: 146070 AF XY: 0.0000888

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.0000806

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000351 AC: 49 AN: 1397206 Hom.: 1 Cov.: 42 AF XY: 0.0000522 AC XY: 36 AN XY: 689586

African (AFR) AF: 0.000158 AC: 5 AN: 31708

American (AMR) AF: 0.0000834 AC: 3 AN: 35972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35888

South Asian (SAS) AF: 0.000314 AC: 25 AN: 79512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1080432

Other (OTH) AF: 0.0000345 AC: 2 AN: 58042

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152232 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000372 AC: 4

ClinVar

ClinVar submissions as Germline

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	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.54		Loss of disorder (P = 0.1168)
MVP		0.52
ClinPred		0.064	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.72
Mutation Taster		=90/10	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: rs753648795; hg19: chr17-80041940; COSMIC: COSV60757668; COSMIC: COSV60757668;