NM_004460.5:c.1651T>C

Variant names:

• chr2-162188332-A-G
• NM_004460.5:c.1651T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004460.5(FAP):​c.1651T>C​(p.Ser551Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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: 1.39
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15139374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5	c.1651T>C	p.Ser551Pro	missense_variant	Exon 20 of 26	ENST00000188790.9	NP_004451.2
FAP	NM_001291807.3	c.1576T>C	p.Ser526Pro	missense_variant	Exon 19 of 25		NP_001278736.1
FAP	XM_011510796.4	c.1621T>C	p.Ser541Pro	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.1651T>C	p.Ser551Pro	missense_variant	Exon 20 of 26	1	NM_004460.5	ENSP00000188790.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1651T>C (p.S551P) alteration is located in exon 20 (coding exon 20) of the FAP gene. This alteration results from a T to C substitution at nucleotide position 1651, causing the serine (S) at amino acid position 551 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	Benign	0.27
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.28	.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.20	T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	.;N;.
PhyloP100		1.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.072
Sift	Benign	0.28	.;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.33
MutPred		0.49		.;Loss of helix (P = 0.1299);.;
MVP		0.61
MPC		0.13
ClinPred		0.41	T
GERP RS		3.4
Varity_R		0.47
gMVP		0.62
Mutation Taster		=81/19	polymorphism

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: chr2-163044842;