5-133199426-C-T

Variant summary

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

The NM_015082.2(FSTL4):c.2198G>A(p.Gly733Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FSTL4 NM_015082.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

FSTL4 (HGNC:21389): (follistatin like 4) Predicted to enable brain-derived neurotrophic factor binding activity and calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to act upstream of or within negative regulation of brain-derived neurotrophic factor receptor signaling pathway; negative regulation of collateral sprouting; and negative regulation of dendritic spine development. Predicted to be located in extracellular region and secretory granule. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

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=0.16589862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSTL4	NM_015082.2	c.2198G>A	p.Gly733Asp	missense_variant	16/16	ENST00000265342.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSTL4	ENST00000265342.12	c.2198G>A	p.Gly733Asp	missense_variant	16/16	5	NM_015082.2	P1
	ENST00000509051.1	n.76-8410C>T		intron_variant, non_coding_transcript_variant		4
FSTL4	ENST00000509525.5	n.1416G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.2198G>A (p.G733D) alteration is located in exon 16 (coding exon 15) of the FSTL4 gene. This alteration results from a G to A substitution at nucleotide position 2198, causing the glycine (G) at amino acid position 733 to be replaced by an aspartic acid (D). 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	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.82	N;.
REVEL	Benign	0.063
Sift	Benign	0.22	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.70	P;.
Vest4		0.10
MutPred		0.37		Loss of catalytic residue at G733 (P = 0.0368);.;
MVP		0.45
MPC		0.39
ClinPred		0.32	T
GERP RS		3.8
Varity_R		0.088
gMVP		0.65

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

Other links and lift over

dbSNP: rs1750248286; hg19: chr5-132535118;