4-161542612-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020116.5(FSTL5):c.1097G>T(p.Gly366Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,782 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: 7.57

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSTL5	NM_020116.5	c.1097G>T	p.Gly366Val	missense_variant	9/16	ENST00000306100.10
FSTL5	NM_001128427.3	c.1094G>T	p.Gly365Val	missense_variant	9/16
FSTL5	NM_001128428.3	c.1094G>T	p.Gly365Val	missense_variant	9/15
FSTL5	XM_011532126.1	c.1097G>T	p.Gly366Val	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSTL5	ENST00000306100.10	c.1097G>T	p.Gly366Val	missense_variant	9/16	1	NM_020116.5	P5
FSTL5	ENST00000379164.8	c.1094G>T	p.Gly365Val	missense_variant	9/16	1		A1
FSTL5	ENST00000427802.2	c.1094G>T	p.Gly365Val	missense_variant	9/15	1		A1
FSTL5	ENST00000511170.1	n.549G>T		non_coding_transcript_exon_variant	5/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000432 AC: 1 AN: 231714 Hom.: 0 AF XY: 0.00000794 AC XY: 1 AN XY: 125906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000332

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417782 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 705430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000488

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Mar 13, 2023

The c.1097G>T (p.G366V) alteration is located in exon 9 (coding exon 8) of the FSTL5 gene. This alteration results from a G to T substitution at nucleotide position 1097, causing the glycine (G) at amino acid position 366 to be replaced by a valine (V). 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	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.6	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.92		Gain of sheet (P = 0.0827);.;.;
MVP		0.96
MPC		0.39
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.87

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: rs1407579471; hg19: chr4-162463764;