chr2-162172846-C-A

Variant names:

• chr2-162172846-C-A
• NM_004460.5:c.2146G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004460.5(FAP):​c.2146G>T​(p.Ala716Ser) 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: 7.45

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

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, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5	c.2146G>T	p.Ala716Ser	missense_variant	Exon 25 of 26	ENST00000188790.9	NP_004451.2
FAP	NM_001291807.3	c.2071G>T	p.Ala691Ser	missense_variant	Exon 24 of 25		NP_001278736.1
FAP	XM_011510796.4	c.2116G>T	p.Ala706Ser	missense_variant	Exon 24 of 25		XP_011509098.1
LOC101929532	NR_110255.1	n.*107C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAP	ENST00000188790.9	c.2146G>T	p.Ala716Ser	missense_variant	Exon 25 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

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2146G>T (p.A716S) alteration is located in exon 25 (coding exon 25) of the FAP gene. This alteration results from a G to T substitution at nucleotide position 2146, causing the alanine (A) at amino acid position 716 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Benign	0.27
Sift	Benign	0.072	.;T;T
Sift4G	Benign	0.094	T;T;T
Polyphen		0.99, 0.93	.;D;P
Vest4		0.81
MutPred		0.65		.;Gain of disorder (P = 0.1174);.;
MVP		0.60
MPC		0.49
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.57
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr2-163029356;