chr4-161500074-G-A

Position:

• chr4-161500074-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020116.5(FSTL5):​c.1400C>T​(p.Pro467Leu) variant causes a missense change involving the alteration of a 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: FSTL5 NM_020116.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSTL5	NM_020116.5	c.1400C>T	p.Pro467Leu	missense_variant	12/16	ENST00000306100.10	NP_064501.2
FSTL5	NM_001128427.3	c.1397C>T	p.Pro466Leu	missense_variant	12/16		NP_001121899.1
FSTL5	NM_001128428.3	c.1370C>T	p.Pro457Leu	missense_variant	11/15		NP_001121900.1
FSTL5	XM_011532126.1	c.1373C>T	p.Pro458Leu	missense_variant	11/15		XP_011530428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSTL5	ENST00000306100.10	c.1400C>T	p.Pro467Leu	missense_variant	12/16	1	NM_020116.5	ENSP00000305334	P5
FSTL5	ENST00000379164.8	c.1397C>T	p.Pro466Leu	missense_variant	12/16	1		ENSP00000368462	A1
FSTL5	ENST00000427802.2	c.1370C>T	p.Pro457Leu	missense_variant	11/15	1		ENSP00000389270	A1
FSTL5	ENST00000511999.1	n.1C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Mar 31, 2023

The c.1400C>T (p.P467L) alteration is located in exon 12 (coding exon 11) of the FSTL5 gene. This alteration results from a C to T substitution at nucleotide position 1400, causing the proline (P) at amino acid position 467 to be replaced by a leucine (L). 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	0.95
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.4	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.77
MutPred		0.47		Gain of stability (P = 0.0144);.;.;
MVP		0.94
MPC		0.36
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.72

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: chr4-162421226; COSMIC: COSV60224793;