5-133199364-C-T

Variant names:

• chr5-133199364-C-T
• rs1487669312
• NM_015082.2:c.2260G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015082.2(FSTL4):​c.2260G>A​(p.Ala754Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FSTL4 NM_015082.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0400

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022030234).
• BP6: Variant 5-133199364-C-T is Benign according to our data. Variant chr5-133199364-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3097348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSTL4	NM_015082.2	c.2260G>A	p.Ala754Thr	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.2260G>A	p.Ala754Thr	missense_variant	Exon 16 of 16	5	NM_015082.2	ENSP00000265342.7
FSTL4	ENST00000509525.5	n.1478G>A		non_coding_transcript_exon_variant	Exon 8 of 8	2
ENSG00000248245	ENST00000509051.1	n.76-8472C>T		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 19, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0060
DANN	Benign	0.82
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.0040
Sift	Benign	0.33	T;.
Sift4G	Benign	0.72	T;T
Polyphen		0.0	B;.
Vest4		0.026
MutPred		0.33		Loss of stability (P = 0.1669);.;
MVP		0.093
MPC		0.22
ClinPred		0.47	T
GERP RS		-1.9
Varity_R		0.030
gMVP		0.35

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

Other links and lift over

dbSNP: rs1487669312; hg19: chr5-132535056;