5-133199354-G-A

Variant names:

• chr5-133199354-G-A
• rs3749817
• NM_015082.2:c.2270C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• Publications: 26 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: 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	c.2270C>T	p.Thr757Met	missense_variant	Exon 16 of 16	ENST00000265342.12	NP_055897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSTL4	ENST00000265342.12	c.2270C>T	p.Thr757Met	missense_variant	Exon 16 of 16	5	NM_015082.2	ENSP00000265342.7
FSTL4	ENST00000509525.5	n.1488C>T		non_coding_transcript_exon_variant	Exon 8 of 8	2
ENSG00000248245	ENST00000509051.1	n.76-8482G>A		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34371 AN: 151974 Hom.: 4818 Cov.: 32

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

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.: 35 AF XY: 0.246 AC XY: 178884 AN XY: 727152

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

GnomAD4 genome AF: 0.226 AC: 34376 AN: 152092 Hom.: 4827 Cov.: 32 AF XY: 0.240 AC XY: 17804 AN XY: 74324

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: 53 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15356 AN: 67976

Other (OTH) AF: 0.240 AC: 505 AN: 2108

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	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.82
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.00025	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		0.34
PrimateAI	Benign	0.25	T
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	T
GERP RS		-6.3
Varity_R		0.018
gMVP		0.25
Mutation Taster		=98/2	polymorphism (auto)

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: rs3749817; hg19: chr5-132535046; COSMIC: COSV54771549; COSMIC: COSV54771549;