5-133199516-C-T

Variant summary

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

The NM_015082.2(FSTL4):c.2108G>A(p.Ser703Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FSTL4 NM_015082.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSTL4	NM_015082.2	c.2108G>A	p.Ser703Asn	missense_variant	16/16	ENST00000265342.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSTL4	ENST00000265342.12	c.2108G>A	p.Ser703Asn	missense_variant	16/16	5	NM_015082.2	P1
	ENST00000509051.1	n.76-8320C>T		intron_variant, non_coding_transcript_variant		4
FSTL4	ENST00000509525.5	n.1326G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

May 30, 2023

The c.2108G>A (p.S703N) 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 2108, causing the serine (S) at amino acid position 703 to be replaced by an asparagine (N). 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	0.75
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.33		Loss of glycosylation at S703 (P = 0.0598);.;
MVP		0.42
MPC		0.76
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.44
gMVP		0.79

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: chr5-132535208; COSMIC: COSV105027924; COSMIC: COSV105027924;