chr2-162174951-C-T

Variant names:

• chr2-162174951-C-T
• rs141879753
• NM_004460.5:c.1885G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004460.5(FAP):​c.1885G>A​(p.Val629Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,611,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: FAP NM_004460.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088891834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5	c.1885G>A	p.Val629Ile	missense_variant	Exon 22 of 26	ENST00000188790.9	NP_004451.2
FAP	NM_001291807.3	c.1810G>A	p.Val604Ile	missense_variant	Exon 21 of 25		NP_001278736.1
FAP	XM_011510796.4	c.1855G>A	p.Val619Ile	missense_variant	Exon 21 of 25		XP_011509098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAP	ENST00000188790.9	c.1885G>A	p.Val629Ile	missense_variant	Exon 22 of 26	1	NM_004460.5	ENSP00000188790.4

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000838 AC: 21 AN: 250718 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135486

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000932 AC: 136 AN: 1459658 Hom.: 0 Cov.: 29 AF XY: 0.0000881 AC XY: 64 AN XY: 726218

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000937

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74386

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000208

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1885G>A (p.V629I) alteration is located in exon 22 (coding exon 22) of the FAP gene. This alteration results from a G to A substitution at nucleotide position 1885, causing the valine (V) at amino acid position 629 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.76	.;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.020	.;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.015, 0.080	.;B;B
Vest4		0.19
MVP		0.36
MPC		0.082
ClinPred		0.049	T
GERP RS		3.6
Varity_R		0.25
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141879753; hg19: chr2-163031461; COSMIC: COSV51859765; COSMIC: COSV51859765;