rs149046822

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004460.5(FAP):​c.1832G>T​(p.Gly611Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G611D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FAP
NM_004460.5 missense

Scores

9
5
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.39
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAPNM_004460.5 linkc.1832G>T p.Gly611Val missense_variant Exon 21 of 26 ENST00000188790.9 NP_004451.2 Q12884-1
FAPNM_001291807.3 linkc.1757G>T p.Gly586Val missense_variant Exon 20 of 25 NP_001278736.1 Q12884B4DLR2
FAPXM_011510796.4 linkc.1802G>T p.Gly601Val missense_variant Exon 20 of 25 XP_011509098.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAPENST00000188790.9 linkc.1832G>T p.Gly611Val missense_variant Exon 21 of 26 1 NM_004460.5 ENSP00000188790.4 Q12884-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457444
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
725196
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
.;T;.
Eigen
Pathogenic
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Uncertain
2.7
.;M;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.7
.;D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0030
.;D;D
Sift4G
Benign
0.074
T;T;T
Polyphen
0.96, 0.36
.;D;B
Vest4
0.81
MVP
0.82
MPC
0.50
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.89
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs149046822; hg19: chr2-163039961; API