chr4-1804404-T-C

Variant names:

• chr4-1804404-T-C
• rs17881656
• NM_000142.5:c.1150T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000142.5(FGFR3):​c.1150T>C​(p.Phe384Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,613,186 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F384I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0045 (30 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.767
• Publications: 93 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000142.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0062094927).
• BP6: Variant 4-1804404-T-C is Benign according to our data. Variant chr4-1804404-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00334 (509/152294) while in subpopulation NFE AF = 0.00615 (418/68010). AF 95% confidence interval is 0.00566. There are 1 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AD,AR,SD gene

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.1150T>C	p.Phe384Leu	missense	Exon 9 of 18	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.1156T>C	p.Phe386Leu	missense	Exon 9 of 18	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.1150T>C	p.Phe384Leu	missense	Exon 9 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.1150T>C	p.Phe384Leu	missense	Exon 9 of 18	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.1150T>C	p.Phe384Leu	missense	Exon 9 of 17	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000352904.6	TSL:1	c.931-420T>C		intron	N/A	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152176 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00615

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00329 AC: 823 AN: 250474 AF XY: 0.00334

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000700

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000791

Gnomad NFE exome AF: 0.00590

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00453 AC: 6620 AN: 1460892 Hom.: 30 Cov.: 36 AF XY: 0.00448 AC XY: 3258 AN XY: 726768

African (AFR) AF: 0.000478 AC: 16 AN: 33470

American (AMR) AF: 0.00302 AC: 135 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000920 AC: 24 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86194

European-Finnish (FIN) AF: 0.000888 AC: 47 AN: 52918

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5760

European-Non Finnish (NFE) AF: 0.00551 AC: 6122 AN: 1111710

Other (OTH) AF: 0.00381 AC: 230 AN: 60362

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152294 Hom.: 1 Cov.: 34 AF XY: 0.00297 AC XY: 221 AN XY: 74470

African (AFR) AF: 0.000866 AC: 36 AN: 41560

American (AMR) AF: 0.00229 AC: 35 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00615 AC: 418 AN: 68010

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00439 Hom.: 1

Bravo AF: 0.00377

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00867

EpiControl AF: 0.00759

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (5)
-	-	1	Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Hypochondroplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.44	N
PhyloP100		0.77
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Benign	0.37	T
Sift4G	Benign	0.48	T
Polyphen		0.0030	B
Vest4		0.092
MutPred		0.16		Gain of sheet (P = 0.039)
MVP		0.81
MPC		0.33
ClinPred		0.010	T
GERP RS		3.6
Varity_R		0.20
gMVP		0.50
Mutation Taster		=75/25	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: rs17881656; hg19: chr4-1806131; COSMIC: COSV53398672; COSMIC: COSV53398672;