chr2-162188338-C-T

Variant summary

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

The NM_004460.5(FAP):​c.1645G>A​(p.Val549Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAP
NM_004460.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAPNM_004460.5 linkc.1645G>A p.Val549Ile missense_variant Exon 20 of 26 ENST00000188790.9 NP_004451.2 Q12884-1
FAPNM_001291807.3 linkc.1570G>A p.Val524Ile missense_variant Exon 19 of 25 NP_001278736.1 Q12884B4DLR2
FAPXM_011510796.4 linkc.1615G>A p.Val539Ile missense_variant Exon 19 of 25 XP_011509098.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAPENST00000188790.9 linkc.1645G>A p.Val549Ile missense_variant Exon 20 of 26 1 NM_004460.5 ENSP00000188790.4 Q12884-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460962
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726762
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1645G>A (p.V549I) alteration is located in exon 20 (coding exon 20) of the FAP gene. This alteration results from a G to A substitution at nucleotide position 1645, causing the valine (V) at amino acid position 549 to be replaced by an isoleucine (I). 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
-0.096
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
.;T;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.0068
T
MetaRNN
Uncertain
0.57
D;D;D
MetaSVM
Benign
-0.55
T
MutationAssessor
Uncertain
2.4
.;M;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.78
.;N;N
REVEL
Uncertain
0.33
Sift
Benign
0.070
.;T;T
Sift4G
Benign
0.074
T;T;T
Polyphen
0.17, 0.94
.;B;P
Vest4
0.71
MutPred
0.72
.;Loss of helix (P = 0.1299);.;
MVP
0.65
MPC
0.46
ClinPred
0.80
D
GERP RS
6.1
Varity_R
0.31
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

hg19: chr2-163044848; API