chr4-161459292-T-C

Position:

• chr4-161459292-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.1636A>G​(p.Lys546Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FSTL5 NM_020116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSTL5	NM_020116.5	c.1636A>G	p.Lys546Glu	missense_variant	14/16	ENST00000306100.10	NP_064501.2
FSTL5	NM_001128427.3	c.1633A>G	p.Lys545Glu	missense_variant	14/16		NP_001121899.1
FSTL5	NM_001128428.3	c.1606A>G	p.Lys536Glu	missense_variant	13/15		NP_001121900.1
FSTL5	XM_011532126.1	c.1609A>G	p.Lys537Glu	missense_variant	13/15		XP_011530428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSTL5	ENST00000306100.10	c.1636A>G	p.Lys546Glu	missense_variant	14/16	1	NM_020116.5	ENSP00000305334.4
FSTL5	ENST00000379164.8	c.1633A>G	p.Lys545Glu	missense_variant	14/16	1		ENSP00000368462.4
FSTL5	ENST00000427802.2	c.1606A>G	p.Lys536Glu	missense_variant	13/15	1		ENSP00000389270.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460818 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726798

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Oct 06, 2024

The c.1636A>G (p.K546E) alteration is located in exon 14 (coding exon 13) of the FSTL5 gene. This alteration results from a A to G substitution at nucleotide position 1636, causing the lysine (K) at amino acid position 546 to be replaced by a glutamic acid (E). 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0060	T;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.88	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.27	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.47	P;.;.
Vest4		0.89
MutPred		0.42		Loss of ubiquitination at K546 (P = 0.0218);.;.;
MVP		0.79
MPC		0.39
ClinPred		0.90	D
GERP RS		4.2
Varity_R		0.27
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1733476802; hg19: chr4-162380444;