5-44388443-T-G

Variant names:

• chr5-44388443-T-G
• rs104893888
• NM_004465.2:c.240A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_004465.2(FGF10):​c.240A>C​(p.Arg80Ser) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGF10 NM_004465.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.901
• Publications: 9 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: Pathogenic. The variant received 10 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
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 5-44388443-T-G is Pathogenic according to our data. Variant chr5-44388443-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7534.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF10	NM_004465.2	c.240A>C	p.Arg80Ser	missense_variant	Exon 1 of 3	ENST00000264664.5	NP_004456.1
FGF10	XM_005248264.5	c.240A>C	p.Arg80Ser	missense_variant	Exon 2 of 4		XP_005248321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF10	ENST00000264664.5	c.240A>C	p.Arg80Ser	missense_variant	Exon 1 of 3	1	NM_004465.2	ENSP00000264664.4
FGF10	ENST00000513107.1	c.*42A>C		downstream_gene_variant		4		ENSP00000426406.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000630 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital absence of salivary gland Pathogenic:1

Mar 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Levy-Hollister syndrome Pathogenic:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

May 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.240A>C (p.R80S) alteration is located in exon 1 (coding exon 1) of the FGF10 gene. This alteration results from a A to C substitution at nucleotide position 240, causing the arginine (R) at amino acid position 80 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in a father and child with reduced/absent tear production, dry mouth, and other features consistent with LADD syndrome (Entesarian, 2007). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.90
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.88		Gain of sheet (P = 0.0827);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		-1.5
Varity_R		0.98
gMVP		0.94
Mutation Taster		=12/88	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: rs104893888; hg19: chr5-44388545;