Genetic Variant NM_015082.2:c.2494G>C (chr5-133199130-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015082.2(FSTL4):c.2494G>C(p.Gly832Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000649 in 1,572,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

FSTL4
NM_015082.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.245

Variant links:

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]

FSTL4 links:

ENSG00000248245 (HGNC:):

ENSG00000248245 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0138629675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSTL4	NM_015082.2 link	c.2494G>C	p.Gly832Arg	missense_variant	Exon 16 of 16	ENST00000265342.12	NP_055897.1	Q6MZW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FSTL4	ENST00000265342.12 link	c.2494G>C	p.Gly832Arg	missense_variant	Exon 16 of 16	5	NM_015082.2	ENSP00000265342.7	Q6MZW2-1
FSTL4	ENST00000509525.5 link	n.1712G>C		non_coding_transcript_exon_variant	Exon 8 of 8	2
ENSG00000248245	ENST00000509051.1 link	n.76-8706C>G		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000672

AC:

AN:

223364

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

118228

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000330

Gnomad SAS exome

AF:

0.0000868

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000396

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000662

AC:

AN:

1420128

Hom.:

Cov.:

AF XY:

0.0000714

AC XY:

AN XY:

700208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000739

Gnomad4 SAS exome

AF:

0.0000508

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000496

Gnomad4 OTH exome

AF:

0.0000683

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.37

DANN

Benign

0.52

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.055

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0096

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;.

PrimateAI

Benign

0.20

PROVEAN

Benign

1.3

N;.

REVEL

Benign

0.12

Sift

Benign

0.86

T;.

Sift4G

Benign

0.92

T;T

Polyphen

0.0

B;.

Vest4

0.038

MutPred

0.36

Gain of MoRF binding (P = 0.0115);.;

MVP

0.17

MPC

0.27

ClinPred

0.0068

GERP RS

-6.0

Varity_R

0.071

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over