NM_004465.2:c.620A>G

Variant names:

• chr5-44305002-T-C
• rs147715509
• NM_004465.2:c.620A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_004465.2(FGF10):​c.620A>G​(p.His207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H207P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: FGF10 NM_004465.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 10 publications found

Genes affected

FGF10 (HGNC:3666): (fibroblast growth factor 10) 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. This protein exhibits mitogenic activity for keratinizing epidermal cells, but essentially no activity for fibroblasts, which is similar to the biological activity of FGF7. Studies of the mouse homolog of suggested that this gene is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of lim bud formation. This gene is also implicated to be a primary factor in the process of wound healing. [provided by RefSeq, Jul 2008]

FGF10 Gene-Disease associations (from GenCC):

• lacrimoauriculodentodigital syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• aplasia of lacrimal and salivary glands

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a chain Fibroblast growth factor 10 (size 170) in uniprot entity FGF10_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_004465.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.85048 (below the threshold of 3.09). Trascript score misZ: 1.4672 (below the threshold of 3.09). GenCC associations: The gene is linked to lacrimoauriculodentodigital syndrome 3, LADD syndrome, aplasia of lacrimal and salivary glands, congenital heart defects, multiple types, craniosynostosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14457113).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004465.2. 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
	FGF10	NM_004465.2	MANE Select	c.620A>G	p.His207Arg	missense	Exon 3 of 3	NP_004456.1	O15520

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF10	ENST00000264664.5	TSL:1 MANE Select	c.620A>G	p.His207Arg	missense	Exon 3 of 3	ENSP00000264664.4	O15520
	FGF10	ENST00000912799.1		c.620A>G	p.His207Arg	missense	Exon 4 of 4	ENSP00000582858.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461566 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111778

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.27
Sift	Benign	0.21	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.36		Gain of MoRF binding (P = 5e-04)
MVP		0.90
MPC		1.5
ClinPred		0.13	T
GERP RS		4.6
Varity_R		0.16
gMVP		0.47
Mutation Taster		=97/3	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: rs147715509; hg19: chr5-44305104;