10-101770490-AGCCCTTGCGGGGCCG-A

Variant names:

• chr10-101770490-AGCCCTTGCGGGGCCG-A
• rs1554834321
• NM_033163.5:c.559_573delCGGCCCCGCAAGGGC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_033163.5(FGF8):​c.559_573delCGGCCCCGCAAGGGC​(p.Arg187_Gly191del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGF8 NM_033163.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.81

Genes affected

FGF8 (HGNC:3686): (fibroblast growth factor 8) 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 is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

LOC105378457 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_033163.5.
• PP5: Variant 10-101770490-AGCCCTTGCGGGGCCG-A is Pathogenic according to our data. Variant chr10-101770490-AGCCCTTGCGGGGCCG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545457.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5	c.559_573delCGGCCCCGCAAGGGC	p.Arg187_Gly191del	conservative_inframe_deletion	Exon 6 of 6	ENST00000320185.7	NP_149353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7	c.559_573delCGGCCCCGCAAGGGC	p.Arg187_Gly191del	conservative_inframe_deletion	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727030

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.559_573del, results in the deletion of 5 amino acid(s) of the FGF8 protein (p.Arg187_Gly191del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of FGF8-related conditions (PMID: 26931467). This variant is also known as c.515-529delCCCGCAAGGGCCGGC. ClinVar contains an entry for this variant (Variation ID: 545457). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FGF8 function (PMID: 26931467). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in siblings with holoprosencephaly in published literature (Hong et al., 2016); Published Zebrafish model showed a complete loss of biological activity (Hong et al., 2016); In-frame deletion of 5 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26931467) -

Holoprosencephaly sequence Pathogenic:1

Apr 18, 2018

Muenke lab, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Family history of similarly affected female sibs with evidence of digenic inheritance of a paternal LOF allele in FGF8 and a maternal LOF allele in FGFR1. Established gene to gene interactions in animal models. This FGF8 variation is supported by experimental data and ACMG criteria: PS3;PM1/PM2/PM4;PP1. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554834321; hg19: chr10-103530247;