NM_004104.5:c.221C>G

Variant names:

• chr17-82095379-G-C
• NM_004104.5:c.221C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004104.5(FASN):​c.221C>G​(p.Thr74Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3784687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.221C>G	p.Thr74Arg	missense_variant	Exon 3 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.221C>G	p.Thr74Arg	missense_variant	Exon 3 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.221C>G	p.Thr74Arg	missense_variant	Exon 3 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.221C>G	p.Thr74Arg	missense_variant	Exon 3 of 43	5		ENSP00000488964.1
FASN	ENST00000635197.1	c.221C>G	p.Thr74Arg	missense_variant	Exon 3 of 4	3		ENSP00000489514.1
FASN	ENST00000637525.1	n.-3C>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460610 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.025	N;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;.;.
REVEL	Benign	0.23
Sift	Benign	0.18	T;.;.
Sift4G	Benign	0.34	T;T;.
Polyphen		1.0	D;.;.
Vest4		0.52
MutPred		0.44		Loss of glycosylation at T74 (P = 0.0742);Loss of glycosylation at T74 (P = 0.0742);Loss of glycosylation at T74 (P = 0.0742);
MVP		0.57
ClinPred		0.75	D
GERP RS		2.9
Varity_R		0.52
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-80053255;