5-133199369-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015082.2(FSTL4):c.2255A>C(p.Tyr752Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 3.24

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSTL4	NM_015082.2	c.2255A>C	p.Tyr752Ser	missense_variant	16/16	ENST00000265342.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSTL4	ENST00000265342.12	c.2255A>C	p.Tyr752Ser	missense_variant	16/16	5	NM_015082.2	P1
	ENST00000509051.1	n.76-8467T>G		intron_variant, non_coding_transcript_variant		4
FSTL4	ENST00000509525.5	n.1473A>C		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

Jan 18, 2022

The c.2255A>C (p.Y752S) alteration is located in exon 16 (coding exon 15) of the FSTL4 gene. This alteration results from a A to C substitution at nucleotide position 2255, causing the tyrosine (Y) at amino acid position 752 to be replaced by a serine (S). 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	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	0.95	D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;.
Vest4		0.58
MutPred		0.62		Gain of disorder (P = 0.0186);.;
MVP		0.52
MPC		0.87
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.65
gMVP		0.86

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: chr5-132535061;