rs28933068

Variant names:

• chr4-1805644-C-A
• rs28933068
• NM_000142.5:c.1620C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1805644-C-A
• chr4-1805644-C-G
• chr4-1805644-C-T

Variant summary

Our verdict is Pathogenic. The variant received 30 ACMG points: 30P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.1620C>A​(p.Asn540Lys) variant causes a missense 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005073893: Functional studies of the variant protein show significant reductions in protein expression, reduced kinase activity, reduced STAT1 phosphorylation and support a damaging effect on the gene or gene product (Krejci P, et al., 2008" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:35 O:1
• Conservation: PhyloP100: 3.02
• Publications: 156 publications found

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]

FGFR3 Gene-Disease associations (from GenCC):

• achondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P, Ambry Genetics, ClinGen
• Crouzon syndrome-acanthosis nigricans syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp, G2P
• hypochondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P, Ambry Genetics
• lacrimoauriculodentodigital syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Muenke syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Genomics England PanelApp
• thanatophoric dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• thanatophoric dysplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Ambry Genetics, Genomics England PanelApp
• thanatophoric dysplasia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• camptodactyly-tall stature-scoliosis-hearing loss syndrome

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• severe achondroplasia-developmental delay-acanthosis nigricans syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 30 ACMG points.

• PS1: Transcript NM_000142.5 (FGFR3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005073893: Functional studies of the variant protein show significant reductions in protein expression, reduced kinase activity, reduced STAT1 phosphorylation and support a damaging effect on the gene or gene product (Krejci P, et al., 2008; Bellus GA, et al., 2000).; SCV005418708: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000321638: Published functional studies demonstrate this variant results in significantly reduced expression patterns and reduced STAT1 phosphorylation (Raffioni et al., 1998; Krejci et al., 2008);; SCV000603707: "functional analyses of the variant protein show significant reductions in protein expression and kinase activity" (Krejci 2008, Raffioni 1998).; SCV002061177: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11055896) - PS3_supporting."; SCV005398096: "This variant has moderate functional evidence supporting abnormal protein function. This variant results in reduced protein expression and protein function compared to the wild type protein (PMID: 9857065)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1805642-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 4-1805644-C-A is Pathogenic according to our data. Variant chr4-1805644-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000142.5. 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
	FGFR3	NM_000142.5	MANE Select	c.1620C>A	p.Asn540Lys	missense	Exon 12 of 18	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.1626C>A	p.Asn542Lys	missense	Exon 12 of 18	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.1623C>A	p.Asn541Lys	missense	Exon 12 of 18	NP_001341738.1	X5D2G8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.1620C>A	p.Asn540Lys	missense	Exon 12 of 18	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.1623C>A	p.Asn541Lys	missense	Exon 12 of 17	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000352904.6	TSL:1	c.1284C>A	p.Asn428Lys	missense	Exon 9 of 15	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250610 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000299 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	not provided (14)
11	-	-	Hypochondroplasia (12)
7	-	-	Achondroplasia (7)
1	-	-	FGFR3-related chondrodysplasia (1)
1	-	-	FGFR3-related disorder (1)
1	-	-	Neurodevelopmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	-0.10	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.90		Gain of methylation at N540 (P = 0.007)
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.81
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs28933068; hg19: chr4-1807371;