4-1793937-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000142.5(FGFR3):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGFR3 NM_000142.5 start_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.0830

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.3G>T	p.Met1?	start_lost	2/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.3G>T	p.Met1?	start_lost	2/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.62e-7 AC: 1 AN: 1159450 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 561054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000701

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Uncertain	0.51	D;T;.;.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;.
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-0.68	N;N;N;N;.;N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.051	B;P;B;B;.;B
Vest4		0.85
MutPred		1.0		Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);
MVP		0.89
ClinPred		0.98	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1560384106; hg19: chr4-1795664;