NM_017559.4:c.889C>G

Variant names:

• chr17-35130348-C-G
• rs374433104
• NM_017559.4:c.889C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017559.4(FNDC8):​c.889C>G​(p.Arg297Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNDC8 NM_017559.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56
• Publications: 0 publications found

Genes affected

FNDC8 (HGNC:25286): (fibronectin type III domain containing 8) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NLE1 (HGNC:19889): (notchless homolog 1) Predicted to be involved in Notch signaling pathway and ribosomal large subunit assembly. Predicted to act upstream of or within several processes, including chordate embryonic development; hematopoietic stem cell homeostasis; and regulation of signal transduction. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017559.4. 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
	FNDC8	NM_017559.4	MANE Select	c.889C>G	p.Arg297Gly	missense	Exon 4 of 4	NP_060029.1	Q8TC99
	NLE1	NM_018096.5	MANE Select	c.*2089G>C		3_prime_UTR	Exon 13 of 13	NP_060566.2	Q9NVX2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNDC8	ENST00000158009.6	TSL:1 MANE Select	c.889C>G	p.Arg297Gly	missense	Exon 4 of 4	ENSP00000158009.4	Q8TC99
	NLE1	ENST00000442241.9	TSL:1 MANE Select	c.*2089G>C		3_prime_UTR	Exon 13 of 13	ENSP00000413572.3	Q9NVX2-1
	NLE1	ENST00000586869.5	TSL:1	c.*2089G>C		3_prime_UTR	Exon 12 of 12	ENSP00000466588.1	Q9NVX2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.47		Gain of sheet (P = 0.0036)
MVP		0.45
MPC		0.60
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.57

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: rs374433104; hg19: chr17-33457367;