4-161500098-T-C

Variant summary

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

The NM_020116.5(FSTL5):c.1376A>G(p.Glu459Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,426 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FSTL5 NM_020116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.89

Genes affected

FSTL5 (HGNC:21386): (follistatin like 5) Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSTL5	NM_020116.5	c.1376A>G	p.Glu459Gly	missense_variant	12/16	ENST00000306100.10
FSTL5	NM_001128427.3	c.1373A>G	p.Glu458Gly	missense_variant	12/16
FSTL5	NM_001128428.3	c.1346A>G	p.Glu449Gly	missense_variant	11/15
FSTL5	XM_011532126.1	c.1349A>G	p.Glu450Gly	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSTL5	ENST00000306100.10	c.1376A>G	p.Glu459Gly	missense_variant	12/16	1	NM_020116.5	P5
FSTL5	ENST00000379164.8	c.1373A>G	p.Glu458Gly	missense_variant	12/16	1		A1
FSTL5	ENST00000427802.2	c.1346A>G	p.Glu449Gly	missense_variant	11/15	1		A1
FSTL5	ENST00000511999.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244222 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131948

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: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454426 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3 AN XY: 723430

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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 03, 2024

The c.1376A>G (p.E459G) alteration is located in exon 12 (coding exon 11) of the FSTL5 gene. This alteration results from a A to G substitution at nucleotide position 1376, causing the glutamic acid (E) at amino acid position 459 to be replaced by a glycine (G). 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	0.23
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.066	T;.;.
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.085	B;.;.
Vest4		0.74
MutPred		0.56		Gain of sheet (P = 0.0344);.;.;
MVP		0.77
MPC		0.37
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768436797; hg19: chr4-162421250;