Genetic Variant FSTL3:p.Gly85Ser (chr19-677941-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005860.3(FSTL3):c.253G>A(p.Gly85Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

FSTL3
NM_005860.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48

Variant links:

Genes affected

FSTL3 (HGNC:3973): (follistatin like 3) Follistatin-like 3 is a secreted glycoprotein of the follistatin-module-protein family. It may have a role in leukemogenesis. [provided by RefSeq, Jul 2008]

FSTL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSTL3	NM_005860.3 link	c.253G>A	p.Gly85Ser	missense_variant	Exon 2 of 5	ENST00000166139.9	NP_005851.1	O95633-1A0A024R1Y8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSTL3	ENST00000166139.9 link	c.253G>A	p.Gly85Ser	missense_variant	Exon 2 of 5	1	NM_005860.3	ENSP00000166139.3		O95633-1
FSTL3	ENST00000592058.3 link	n.-120G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250628

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135664

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1461158

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253G>A (p.G85S) alteration is located in exon 2 (coding exon 2) of the FSTL3 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the glycine (G) at amino acid position 85 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

Benign

0.15

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.70

Sift

Benign

0.39

Sift4G

Benign

0.082

Polyphen

1.0

Vest4

0.62

MutPred

0.61

Gain of catalytic residue at G85 (P = 0.1189);

MVP

0.91

MPC

1.5

ClinPred

0.96

GERP RS

4.3

Varity_R

0.43

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over