15-82765927-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001007122.4(FSD2):​c.1658G>A​(p.Arg553Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,400 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 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FSD2
NM_001007122.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02
Variant links:
Genes affected
FSD2 (HGNC:18024): (fibronectin type III and SPRY domain containing 2) This gene encodes a protein that belongs to the FN3/SPRY family of proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3743974).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FSD2NM_001007122.4 linkc.1658G>A p.Arg553Lys missense_variant Exon 10 of 13 ENST00000334574.12 NP_001007123.1 A1L4K1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FSD2ENST00000334574.12 linkc.1658G>A p.Arg553Lys missense_variant Exon 10 of 13 1 NM_001007122.4 ENSP00000335651.8 A1L4K1-1
FSD2ENST00000541889.1 linkc.1523G>A p.Arg508Lys missense_variant Exon 9 of 12 1 ENSP00000444078.1 A1L4K1-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00000412
AC:
1
AN:
242428
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131614
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000906
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1458180
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
725024
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
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
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 30, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1658G>A (p.R553K) alteration is located in exon 10 (coding exon 9) of the FSD2 gene. This alteration results from a G to A substitution at nucleotide position 1658, causing the arginine (R) at amino acid position 553 to be replaced by a lysine (K). 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
0.12
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.79
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.37
T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
1.9
L;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.68
N;N
REVEL
Benign
0.18
Sift
Benign
0.047
D;D
Sift4G
Uncertain
0.046
D;D
Polyphen
1.0
D;.
Vest4
0.34
MutPred
0.36
Gain of ubiquitination at R553 (P = 0.017);.;
MVP
0.37
MPC
0.18
ClinPred
0.82
D
GERP RS
5.6
Varity_R
0.28
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

LitVar

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

Other links and lift over

dbSNP: rs1330606951; hg19: chr15-83434679; API