Genetic Variant NM_015082.2:c.2270C>T (chr5-133199354-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015082.2(FSTL4):c.2270C>T(p.Thr757Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,760 control chromosomes in the GnomAD database, including 53,861 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.23 ( 4827 hom., cov: 32)

Exomes 𝑓: 0.24 ( 49034 hom. )

Consequence

FSTL4
NM_015082.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.338

Publications

26 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.4548173E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSTL4	NM_015082.2 link	c.2270C>T	p.Thr757Met	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.2270C>T	p.Thr757Met	missense_variant	Exon 16 of 16	5	NM_015082.2	ENSP00000265342.7	Q6MZW2-1
FSTL4	ENST00000509525.5 link	n.1488C>T		non_coding_transcript_exon_variant	Exon 8 of 8	2
ENSG00000248245	ENST00000509051.1 link	n.76-8482G>A		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34371

AN:

151974

Hom.:

4818

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0868

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.441

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.226

Gnomad OTH

AF:

0.240

GnomAD2 exomes

AF:

0.305

AC:

76724

AN:

251278

AF XY:

0.300

show subpopulations

Gnomad AFR exome

AF:

0.0818

Gnomad AMR exome

AF:

0.503

Gnomad ASJ exome

AF:

0.311

Gnomad EAS exome

AF:

0.448

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.227

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.244

AC:

356719

AN:

1461668

Hom.:

49034

Cov.:

AF XY:

0.246

AC XY:

178884

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.0788

AC:

2637

AN:

33480

American (AMR)

AF:

0.485

AC:

21683

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8148

AN:

26136

East Asian (EAS)

AF:

0.477

AC:

18928

AN:

39696

South Asian (SAS)

AF:

0.333

AC:

28710

AN:

86252

European-Finnish (FIN)

AF:

0.400

AC:

21384

AN:

53404

Middle Eastern (MID)

AF:

0.223

AC:

1286

AN:

5768

European-Non Finnish (NFE)

AF:

0.215

AC:

238924

AN:

1111832

Other (OTH)

AF:

0.249

AC:

15019

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

16688

33376

50065

66753

83441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8454

16908

25362

33816

42270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34376

AN:

152092

Hom.:

4827

Cov.:

AF XY:

0.240

AC XY:

17804

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0865

AC:

3591

AN:

41528

American (AMR)

AF:

0.343

AC:

5240

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1058

AN:

3468

East Asian (EAS)

AF:

0.440

AC:

2268

AN:

5150

South Asian (SAS)

AF:

0.352

AC:

1693

AN:

4812

European-Finnish (FIN)

AF:

0.415

AC:

4385

AN:

10558

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.226

AC:

15356

AN:

67976

Other (OTH)

AF:

0.240

AC:

505

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1295

2589

3884

5178

6473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.230

Hom.:

20185

Bravo

AF:

0.219

TwinsUK

AF:

0.217

AC:

804

ALSPAC

AF:

0.212

AC:

817

ESP6500AA

AF:

0.0872

AC:

384

ESP6500EA

AF:

0.217

AC:

1863

ExAC

AF:

0.291

AC:

35353

Asia WGS

AF:

0.343

AC:

1195

AN:

3478

EpiCase

AF:

0.219

EpiControl

AF:

0.224

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.1

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.45

T;T

MetaRNN

Benign

0.00025

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

L;.

PhyloP100

0.34

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.82

N;.

REVEL

Benign

0.023

Sift

Benign

0.13

T;.

Sift4G

Benign

0.29

T;T

Polyphen

0.014

B;.

Vest4

0.080

MPC

0.24

ClinPred

0.011

GERP RS

-6.3

Varity_R

0.018

gMVP

0.25

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over