Genetic Variant FAP:p.Met567Lys (chr2-162188283-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004460.5(FAP):c.1700T>A(p.Met567Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M567T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FAP
NM_004460.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.71

Publications

0 publications found

Variant links:

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]

FAP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5 link	c.1700T>A	p.Met567Lys	missense_variant	Exon 20 of 26	ENST00000188790.9	NP_004451.2	Q12884-1
FAP	NM_001291807.3 link	c.1625T>A	p.Met542Lys	missense_variant	Exon 19 of 25		NP_001278736.1	Q12884B4DLR2
FAP	XM_011510796.4 link	c.1670T>A	p.Met557Lys	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 link	c.1700T>A	p.Met567Lys	missense_variant	Exon 20 of 26	1	NM_004460.5	ENSP00000188790.4		Q12884-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111558

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.37

.;T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.0080

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

.;N;.

PhyloP100

8.7

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.6

.;D;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.51, 0.010

.;P;B

Vest4

0.82

MutPred

0.86

.;Gain of catalytic residue at M567 (P = 0.0296);.;

MVP

0.48

MPC

0.33

ClinPred

0.97

GERP RS

6.1

Varity_R

0.93

gMVP

0.73

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr2-162188283-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over