11-69774948-C-T

Variant names:

• chr11-69774948-C-T
• rs1054010007
• NM_002007.4:c.137G>A

Variant summary

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

The NM_002007.4(FGF4):​c.137G>A​(p.Arg46His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R46L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGF4 NM_002007.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

Genes affected

FGF4 (HGNC:3682): (fibroblast growth factor 4) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway. [provided by RefSeq, Jul 2008]

FGF4 Gene-Disease associations (from GenCC):

• thoracic malformation

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002007.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF4	NM_002007.4	MANE Select	c.137G>A	p.Arg46His	missense	Exon 1 of 3	NP_001998.1	P08620-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF4	ENST00000168712.3	TSL:1 MANE Select	c.137G>A	p.Arg46His	missense	Exon 1 of 3	ENSP00000168712.1	P08620-1
	FGF4	ENST00000538040.1	TSL:1	n.217G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1325344 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 653568

African (AFR) AF: 0.00 AC: 0 AN: 26692

American (AMR) AF: 0.00 AC: 0 AN: 27582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23216

East Asian (EAS) AF: 0.00 AC: 0 AN: 28524

South Asian (SAS) AF: 0.00 AC: 0 AN: 73396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1053862

Other (OTH) AF: 0.00 AC: 0 AN: 55044

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.028
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.087	T
Polyphen		0.99	D
Vest4		0.042
MutPred		0.46		Loss of stability (P = 0.0591)
MVP		0.74
MPC		0.99
ClinPred		0.60	D
GERP RS		3.2
PromoterAI		-0.0050	Neutral
Varity_R		0.15
gMVP		0.61
Mutation Taster		=80/20	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

dbSNP: rs1054010007; hg19: chr11-69589716; COSMIC: COSV108768111;