chr17-35130348-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC8	NM_017559.4	c.889C>G	p.Arg297Gly	missense_variant	Exon 4 of 4	ENST00000158009.6	NP_060029.1
NLE1	NM_018096.5	c.*2089G>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000442241.9	NP_060566.2
NLE1	XM_017024777.2	c.*2089G>C		3_prime_UTR_variant	Exon 11 of 11		XP_016880266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNDC8	ENST00000158009.6	c.889C>G	p.Arg297Gly	missense_variant	Exon 4 of 4	1	NM_017559.4	ENSP00000158009.4
NLE1	ENST00000442241	c.*2089G>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_018096.5	ENSP00000413572.3
NLE1	ENST00000586869	c.*2089G>C		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000466588.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.889C>G (p.R297G) alteration is located in exon 4 (coding exon 4) of the FNDC8 gene. This alteration results from a C to G substitution at nucleotide position 889, causing the arginine (R) at amino acid position 297 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-33457367;