Variant chr2-162189745-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004460.5(FAP):c.1460T>A(p.Ile487Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000257 in 1,558,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FAP
NM_004460.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.84

Variant links:

Genes affected

FAP (HGNC:3590): (fibroblast activation protein alpha) The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. This protein is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

FAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4039916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAP	NM_004460.5 link	c.1460T>A	p.Ile487Asn	missense_variant	18/26	ENST00000188790.9	NP_004451.2	Q12884-1
FAP	NM_001291807.3 link	c.1385T>A	p.Ile462Asn	missense_variant	17/25		NP_001278736.1	Q12884B4DLR2
FAP	XM_011510796.4 link	c.1430T>A	p.Ile477Asn	missense_variant	17/25		XP_011509098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAP	ENST00000188790.9 link	c.1460T>A	p.Ile487Asn	missense_variant	18/26	1	NM_004460.5	ENSP00000188790.4		Q12884-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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

GnomAD3 exomes

AF:

0.0000129

AC:

AN:

232636

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

125840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000983

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1406180

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

701320

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000727

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.1460T>A (p.I487N) alteration is located in exon 18 (coding exon 18) of the FAP gene. This alteration results from a T to A substitution at nucleotide position 1460, causing the isoleucine (I) at amino acid position 487 to be replaced by an asparagine (N). 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

0.19

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.69

.;D;.

Eigen

Benign

0.096

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.3

.;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.7

.;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.014

.;D;D

Sift4G

Benign

0.095

T;T;T

Polyphen

0.046, 0.0020

.;B;B

Vest4

0.65

MVP

0.98

MPC

0.42

ClinPred

0.91

GERP RS

5.5

Varity_R

0.77

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over