2-112185305-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153214.3(FBLN7):c.913A>C(p.Ser305Arg) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBLN7 NM_153214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

Genes affected

FBLN7 (HGNC:26740): (fibulin 7) Predicted to enable calcium ion binding activity; heparan sulfate proteoglycan binding activity; and heparin binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within positive regulation of biomineralization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22499624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBLN7	NM_153214.3	c.913A>C	p.Ser305Arg	missense_variant	7/8	ENST00000331203.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN7	ENST00000331203.7	c.913A>C	p.Ser305Arg	missense_variant	7/8	1	NM_153214.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.913A>C (p.S305R) alteration is located in exon 7 (coding exon 7) of the FBLN7 gene. This alteration results from a A to C substitution at nucleotide position 913, causing the serine (S) at amino acid position 305 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0057	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.
MutationTaster	Benign	0.72	D;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.70	N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.59	T;T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T
Polyphen		0.019	B;P;B;B;.;.
Vest4		0.48
MutPred		0.37		Loss of glycosylation at S305 (P = 0.0076);Loss of glycosylation at S305 (P = 0.0076);.;.;.;.;
MVP		0.82
MPC		0.74
ClinPred		0.70	D
GERP RS		4.2
Varity_R		0.13
gMVP		0.50

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: rs1683216817; hg19: chr2-112942882;