19-4304760-G-A

Variant names:

• chr19-4304760-G-A
• NM_024333.3:c.14G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024333.3(FSD1):​c.14G>A​(p.Arg5Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000001 in 995,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: FSD1 NM_024333.3 missense, splice_region
• Scores: Splicing: ADA: 0.004072
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.680

Genes affected

FSD1 (HGNC:13745): (fibronectin type III and SPRY domain containing 1) This gene encodes a centrosome associated protein that is characterized by an N-terminal coiled-coil region downstream of B-box (BBC) domain, a central fibronectin type III domain, and a C-terminal repeats in splA and RyR (SPRY) domain. The encoded protein associates with a subset of microtubules and may be involved in the stability and organization of microtubules during cytokinesis. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03001675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSD1	NM_024333.3	c.14G>A	p.Arg5Lys	missense_variant, splice_region_variant	Exon 1 of 13	ENST00000221856.11	NP_077309.1
FSD1	NM_001330429.2	c.14G>A	p.Arg5Lys	missense_variant, splice_region_variant	Exon 1 of 13		NP_001317358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSD1	ENST00000221856.11	c.14G>A	p.Arg5Lys	missense_variant, splice_region_variant	Exon 1 of 13	1	NM_024333.3	ENSP00000221856.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000100 AC: 1 AN: 995230 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 472038

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14G>A (p.R5K) alteration is located in exon 1 (coding exon 1) of the FSD1 gene. This alteration results from a G to A substitution at nucleotide position 14, causing the arginine (R) at amino acid position 5 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	0.099
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.23	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.72	N;.;.
REVEL	Benign	0.041
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.093
MutPred		0.47		Gain of methylation at R5 (P = 0.0199);Gain of methylation at R5 (P = 0.0199);Gain of methylation at R5 (P = 0.0199);
MVP		0.043
MPC		0.46
ClinPred		0.081	T
GERP RS		0.87
Varity_R		0.10
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.25
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: chr19-4304757;