17-7442673-G-T

Position:

• chr17-7442673-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000293829.9(FGF11):​c.488G>T​(p.Arg163Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGF11 ENST00000293829.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50

Genes affected

FGF11 (HGNC:3667): (fibroblast growth factor 11) 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. The function of this gene has not yet been determined. The expression pattern of the mouse homolog implies a role in nervous system development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF11	NM_004112.4	c.488G>T	p.Arg163Leu	missense_variant	4/5	ENST00000293829.9	NP_004103.1
FGF11	NM_001303460.2	c.311G>T	p.Arg104Leu	missense_variant	4/5		NP_001290389.1
FGF11	NR_130156.2	n.528G>T		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF11	ENST00000293829.9	c.488G>T	p.Arg163Leu	missense_variant	4/5	1	NM_004112.4	ENSP00000293829	P1
	ENST00000576615.1	n.69+586C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.488G>T (p.R163L) alteration is located in exon 4 (coding exon 4) of the FGF11 gene. This alteration results from a G to T substitution at nucleotide position 488, causing the arginine (R) at amino acid position 163 to be replaced by a leucine (L). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	.;D;.;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	.;D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.79
MutPred		0.55		.;Loss of MoRF binding (P = 0.0337);.;.;.;
MVP		0.93
MPC		0.60
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.72
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs548703936; hg19: chr17-7345992;