17-35129470-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017559.4(FNDC8):​c.634C>T​(p.Leu212Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FNDC8
NM_017559.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.18198663).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FNDC8NM_017559.4 linkc.634C>T p.Leu212Phe missense_variant Exon 3 of 4 ENST00000158009.6 NP_060029.1 Q8TC99
NLE1NM_018096.5 linkc.*2967G>A 3_prime_UTR_variant Exon 13 of 13 ENST00000442241.9 NP_060566.2 Q9NVX2-1
NLE1XM_017024777.2 linkc.*2967G>A 3_prime_UTR_variant Exon 11 of 11 XP_016880266.1 Q9NVX2-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FNDC8ENST00000158009.6 linkc.634C>T p.Leu212Phe missense_variant Exon 3 of 4 1 NM_017559.4 ENSP00000158009.4 Q8TC99
NLE1ENST00000442241 linkc.*2967G>A 3_prime_UTR_variant Exon 13 of 13 1 NM_018096.5 ENSP00000413572.3 Q9NVX2-1
NLE1ENST00000586869 linkc.*2967G>A 3_prime_UTR_variant Exon 12 of 12 1 ENSP00000466588.1 Q9NVX2-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251484
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461888
Hom.:
0
Cov.:
30
AF XY:
0.0000165
AC XY:
12
AN XY:
727244
show subpopulations
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:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.634C>T (p.L212F) alteration is located in exon 3 (coding exon 3) of the FNDC8 gene. This alteration results from a C to T substitution at nucleotide position 634, causing the leucine (L) at amino acid position 212 to be replaced by a phenylalanine (F). 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
0.57
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.13
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.018
D
Polyphen
0.055
B
Vest4
0.26
MutPred
0.61
Gain of relative solvent accessibility (P = 0.1259);
MVP
0.60
MPC
0.18
ClinPred
0.26
T
GERP RS
4.3
Varity_R
0.15
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756566725; hg19: chr17-33456489; API