17-35121743-T-A

Variant names:

• chr17-35121743-T-A
• NM_017559.4:c.50T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017559.4(FNDC8):​c.50T>A​(p.Leu17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 0.751

Genes affected

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

ENSG00000267618 (HGNC:):

RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22989428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC8	NM_017559.4	c.50T>A	p.Leu17Gln	missense_variant	Exon 1 of 4	ENST00000158009.6	NP_060029.1
RAD51L3-RFFL	NR_037714.1	n.-221A>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNDC8	ENST00000158009.6	c.50T>A	p.Leu17Gln	missense_variant	Exon 1 of 4	1	NM_017559.4	ENSP00000158009.4
ENSG00000267618	ENST00000593039.5	c.-450A>T		upstream_gene_variant		2		ENSP00000466834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50T>A (p.L17Q) alteration is located in exon 1 (coding exon 1) of the FNDC8 gene. This alteration results from a T to A substitution at nucleotide position 50, causing the leucine (L) at amino acid position 17 to be replaced by a glutamine (Q). 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	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.083
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.034	D
Polyphen		0.84	P
Vest4		0.30
MutPred		0.28		Gain of solvent accessibility (P = 0.0374);
MVP		0.30
MPC		0.12
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.20
gMVP		0.50

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: chr17-33448762;