chr2-162171007-A-G

Variant names:

• chr2-162171007-A-G
• NM_004460.5:c.2255T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004460.5(FAP):​c.2255T>C​(p.Leu752Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAP NM_004460.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.80
• 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]

ENSG00000236841 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5	c.2255T>C	p.Leu752Pro	missense_variant	Exon 26 of 26	ENST00000188790.9	NP_004451.2
FAP	NM_001291807.3	c.2180T>C	p.Leu727Pro	missense_variant	Exon 25 of 25		NP_001278736.1
FAP	XM_011510796.4	c.2225T>C	p.Leu742Pro	missense_variant	Exon 25 of 25		XP_011509098.1
LOC101929532	NR_110255.1	n.1877A>G		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAP	ENST00000188790.9	c.2255T>C	p.Leu752Pro	missense_variant	Exon 26 of 26	1	NM_004460.5	ENSP00000188790.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2255T>C (p.L752P) alteration is located in exon 26 (coding exon 26) of the FAP gene. This alteration results from a T to C substitution at nucleotide position 2255, causing the leucine (L) at amino acid position 752 to be replaced by a proline (P). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	.;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.9	.;H;.
PhyloP100		8.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.3	.;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92
MutPred		0.84		.;Loss of catalytic residue at L752 (P = 0.0079);.;
MVP		0.93
MPC		0.65
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.80
Mutation Taster		=27/73	disease causing

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

Other links and lift over

hg19: chr2-163027517;