5-133199130-C-A

Variant names:

• chr5-133199130-C-A
• rs558686290
• NM_015082.2:c.2494G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015082.2(FSTL4):​c.2494G>T​(p.Gly832Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000636 in 1,572,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G832R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: FSTL4 NM_015082.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.245
• Publications: 0 publications found

Genes affected

FSTL4 (HGNC:21389): (follistatin like 4) Predicted to enable brain-derived neurotrophic factor binding activity and calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to act upstream of or within negative regulation of brain-derived neurotrophic factor receptor signaling pathway; negative regulation of collateral sprouting; and negative regulation of dendritic spine development. Predicted to be located in extracellular region and secretory granule. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000248245 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106972516).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015082.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSTL4	NM_015082.2	MANE Select	c.2494G>T	p.Gly832Trp	missense	Exon 16 of 16	NP_055897.1	Q6MZW2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSTL4	ENST00000265342.12	TSL:5 MANE Select	c.2494G>T	p.Gly832Trp	missense	Exon 16 of 16	ENSP00000265342.7	Q6MZW2-1
	FSTL4	ENST00000897474.1		c.2596G>T	p.Gly866Trp	missense	Exon 15 of 15	ENSP00000567533.1
	FSTL4	ENST00000897473.1		c.2467G>T	p.Gly823Trp	missense	Exon 15 of 15	ENSP00000567532.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 223364 AF XY: 0.0000254

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000493 AC: 7 AN: 1420128 Hom.: 0 Cov.: 31 AF XY: 0.00000428 AC XY: 3 AN XY: 700208

African (AFR) AF: 0.00 AC: 0 AN: 32882

American (AMR) AF: 0.0000235 AC: 1 AN: 42628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23350

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00 AC: 0 AN: 78682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4958

European-Non Finnish (NFE) AF: 0.00000460 AC: 5 AN: 1088034

Other (OTH) AF: 0.0000171 AC: 1 AN: 58536

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74422

African (AFR) AF: 0.0000722 AC: 3 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000392 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.076	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.24
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.024	D
Polyphen		0.91	P
Vest4		0.24
MutPred		0.41		Gain of MoRF binding (P = 0.028)
MVP		0.24
MPC		0.65
ClinPred		0.47	T
GERP RS		-6.0
Varity_R		0.096
gMVP		0.56
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs558686290; hg19: chr5-132534822; COSMIC: COSV54768499; COSMIC: COSV54768499;