Genetic Variant FN1:p.Ala26Thr (chr2-215435727-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_212482.4(FN1):c.76G>A(p.Ala26Thr) 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: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

FN1
NM_212482.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00100

Variant links:

Genes affected

FN1 (HGNC:3778): (fibronectin 1) This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined. [provided by RefSeq, Jan 2016]

FN1 links:

FN1-DT (HGNC:55775): (FN1 divergent transcript)

FN1-DT links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04817891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4 link	c.76G>A	p.Ala26Thr	missense_variant	Exon 1 of 46	ENST00000354785.11	NP_997647.2	P02751-15Q6MZM7Q9UQS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11 link	c.76G>A	p.Ala26Thr	missense_variant	Exon 1 of 46	1	NM_212482.4	ENSP00000346839.4		P02751-15

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152166

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 26 of the FN1 protein (p.Ala26Thr). This variant has not been reported in the literature in individuals affected with FN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

.;.;.;.;.;T;.;.;.;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.85

T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.048

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.31

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.038

Sift

Benign

0.31

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.94

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;D;B;.;.;B;B;B;.

Vest4

0.041

MutPred

0.13

Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);

MVP

0.45

MPC

0.25

ClinPred

0.066

GERP RS

-2.8

Varity_R

0.12

gMVP

0.079

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over