4-1793996-C-A

Variant names:

• chr4-1793996-C-A
• rs587778351
• NM_000142.5:c.62C>A

Variant summary

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

The NM_000142.5(FGFR3):​c.62C>A​(p.Ser21Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,242,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.374

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 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=0.24342719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.62C>A	p.Ser21Tyr	missense_variant	Exon 2 of 18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.62C>A	p.Ser21Tyr	missense_variant	Exon 2 of 18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.05e-7 AC: 1 AN: 1242946 Hom.: 0 Cov.: 30 AF XY: 0.00000164 AC XY: 1 AN XY: 608210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T;T;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.81	T;T;T;T;T;.
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N;.;N;N;.;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.36	N;N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.053	T;D;D;D;.;D
Sift4G	Benign	0.98	T;T;T;T;T;T
Polyphen		0.054	B;B;P;D;.;D
Vest4		0.29
MutPred		0.38		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.69
MPC		0.52
ClinPred		0.16	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.25

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: rs587778351; hg19: chr4-1795723;