chr2-162173752-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004460.5(FAP):c.2005A>G(p.Thr669Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,596 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FAP
NM_004460.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25401193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5 link	c.2005A>G	p.Thr669Ala	missense_variant	Exon 23 of 26	ENST00000188790.9	NP_004451.2	Q12884-1
FAP	NM_001291807.3 link	c.1930A>G	p.Thr644Ala	missense_variant	Exon 22 of 25		NP_001278736.1	Q12884B4DLR2
FAP	XM_011510796.4 link	c.1975A>G	p.Thr659Ala	missense_variant	Exon 22 of 25		XP_011509098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAP	ENST00000188790.9 link	c.2005A>G	p.Thr669Ala	missense_variant	Exon 23 of 26	1	NM_004460.5	ENSP00000188790.4		Q12884-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453596

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723712

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1104680

Other (OTH)

AF:

0.00

AC:

AN:

60084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.018668), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2005A>G (p.T669A) alteration is located in exon 23 (coding exon 23) of the FAP gene. This alteration results from a A to G substitution at nucleotide position 2005, causing the threonine (T) at amino acid position 669 to be replaced by an alanine (A). 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

0.092

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

.;T;.

Eigen

Benign

-0.058

Eigen_PC

Benign

0.071

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L;.

PhyloP100

2.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

.;N;N

REVEL

Benign

0.10

Sift

Benign

0.18

.;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.19, 0.87

.;B;P

Vest4

0.38

MutPred

0.50

.;Loss of phosphorylation at T669 (P = 0.0516);.;

MVP

0.42

MPC

0.13

ClinPred

0.72

GERP RS

5.2

Varity_R

0.18

gMVP

0.36

Mutation Taster

=65/35

polymorphism

(source)

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

Publications

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chr2-162173752-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over