2-112159707-C-T

Position:

• chr2-112159707-C-T

Variant summary

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

The NM_153214.3(FBLN7):​c.107C>T​(p.Ala36Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,425,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBLN7 NM_153214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

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=0.23904917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN7	NM_153214.3	c.107C>T	p.Ala36Val	missense_variant	2/8	ENST00000331203.7	NP_694946.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN7	ENST00000331203.7	c.107C>T	p.Ala36Val	missense_variant	2/8	1	NM_153214.3	ENSP00000331411	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1425548 Hom.: 0 Cov.: 30 AF XY: 0.00000423 AC XY: 3 AN XY: 708576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 31, 2022

The c.107C>T (p.A36V) alteration is located in exon 2 (coding exon 2) of the FBLN7 gene. This alteration results from a C to T substitution at nucleotide position 107, causing the alanine (A) at amino acid position 36 to be replaced by a valine (V). 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	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;.;.;.
Eigen	Benign	-0.037
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.85	T;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.2	L;.;L;L
MutationTaster	Benign	0.61	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.0090	B;B;B;B
Vest4		0.18
MutPred		0.68		Loss of disorder (P = 0.0327);Loss of disorder (P = 0.0327);Loss of disorder (P = 0.0327);Loss of disorder (P = 0.0327);
MVP		0.88
MPC		0.29
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.17
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1681624852; hg19: chr2-112917284;