1-32868336-C-G

Variant names:

• chr1-32868336-C-G
• rs1483924274
• NM_153756.3:c.263G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153756.3(FNDC5):​c.263G>C​(p.Arg88Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNDC5 NM_153756.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.55
• Publications: 0 publications found

Genes affected

FNDC5 (HGNC:20240): (fibronectin type III domain containing 5) This gene encodes a secreted protein that is released from muscle cells during exercise. The encoded protein may participate in the development of brown fat. Translation of the precursor protein initiates at a non-AUG start codon at a position that is conserved as an AUG start codon in other organisms. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153756.3. 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
	FNDC5	NM_153756.3	MANE Select	c.263G>C	p.Arg88Pro	missense	Exon 3 of 6	NP_715637.2	A0A0A0MRR6
	FNDC5	NM_001441683.1		c.407G>C	p.Arg136Pro	missense	Exon 3 of 6	NP_001428612.1
	FNDC5	NM_001436107.1		c.263G>C	p.Arg88Pro	missense	Exon 3 of 6	NP_001423036.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNDC5	ENST00000373471.9	TSL:2 MANE Select	c.263G>C	p.Arg88Pro	missense	Exon 3 of 6	ENSP00000362570.5	A0A0A0MRR6
	FNDC5	ENST00000496770.1	TSL:1	c.38G>C	p.Arg13Pro	missense	Exon 3 of 5	ENSP00000476320.1	Q8NAU1-3
	FNDC5	ENST00000710568.1		c.407G>C	p.Arg136Pro	missense	Exon 3 of 6	ENSP00000518350.1	Q8NAU1-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.6
PrimateAI	Pathogenic	0.88	D
REVEL	Pathogenic	0.69
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.45
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.72
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1483924274; hg19: chr1-33333937;