chr2-162188338-C-T

Variant names:

• chr2-162188338-C-T
• rs771148895
• NM_004460.5:c.1645G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004460.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAP	NM_004460.5	MANE Select	c.1645G>A	p.Val549Ile	missense	Exon 20 of 26	NP_004451.2
	FAP	NM_001291807.3		c.1570G>A	p.Val524Ile	missense	Exon 19 of 25	NP_001278736.1	B4DLR2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAP	ENST00000188790.9	TSL:1 MANE Select	c.1645G>A	p.Val549Ile	missense	Exon 20 of 26	ENSP00000188790.4	Q12884-1
	FAP	ENST00000422436.5	TSL:1	n.*526G>A		non_coding_transcript_exon	Exon 7 of 13	ENSP00000417028.1	H7C4D9
	FAP	ENST00000422436.5	TSL:1	n.*526G>A		3_prime_UTR	Exon 7 of 13	ENSP00000417028.1	H7C4D9

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

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111446

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0068	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.33
Sift	Benign	0.070	T
Sift4G	Benign	0.074	T
Polyphen		0.17	B
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
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs771148895; hg19: chr2-163044848;