chr2-162188338-C-T

Variant names:

• chr2-162188338-C-T
• NM_004460.5:c.1645G>A

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50

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]

ACMG classification

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
FAP	NM_004460.5	c.1645G>A	p.Val549Ile	missense_variant	Exon 20 of 26	ENST00000188790.9	NP_004451.2
FAP	NM_001291807.3	c.1570G>A	p.Val524Ile	missense_variant	Exon 19 of 25		NP_001278736.1
FAP	XM_011510796.4	c.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
FAP	ENST00000188790.9	c.1645G>A	p.Val549Ile	missense_variant	Exon 20 of 26	1	NM_004460.5	ENSP00000188790.4

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

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

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;