rs4664454

Variant names:

• chr2-162214651-C-G
• rs4664454
• NM_004460.5:c.867-578G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004460.5(FAP):​c.867-578G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 150,378 control chromosomes in the GnomAD database, including 465 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.036 (465 hom., cov: 32)
• Consequence: FAP NM_004460.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAP	NM_004460.5	c.867-578G>C		intron_variant	Intron 10 of 25	ENST00000188790.9	NP_004451.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAP	ENST00000188790.9	c.867-578G>C		intron_variant	Intron 10 of 25	1	NM_004460.5	ENSP00000188790.4
FAP	ENST00000480838.1	n.854-578G>C		intron_variant	Intron 9 of 10	1
FAP	ENST00000443424.5	c.792-578G>C		intron_variant	Intron 9 of 24	2		ENSP00000411391.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5383 AN: 150260 Hom.: 449 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00993

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.00578

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0200

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0455

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0361 AC: 5425 AN: 150378 Hom.: 465 Cov.: 32 AF XY: 0.0390 AC XY: 2860 AN XY: 73284

African (AFR) AF: 0.0107 AC: 436 AN: 40844

American (AMR) AF: 0.214 AC: 3184 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 20 AN: 3460

East Asian (EAS) AF: 0.122 AC: 622 AN: 5108

South Asian (SAS) AF: 0.0204 AC: 96 AN: 4698

European-Finnish (FIN) AF: 0.0122 AC: 127 AN: 10374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 822 AN: 67758

Other (OTH) AF: 0.0527 AC: 109 AN: 2068

Alfa AF: 0.0269 Hom.: 34

Bravo AF: 0.0547

Asia WGS AF: 0.112 AC: 388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.44
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4664454; hg19: chr2-163071161;