10-101770593-GAC-AAA

Variant names:

• chr10-101770593-GAC-AAA
• NM_033163.5:c.469_471delGTCinsTTT
• FGF8 p.Val157Phe

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PP2 PP3

The NM_033163.5(FGF8):​c.469_471delGTCinsTTT​(p.Val157Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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. V157I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGF8 NM_033163.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.88
• Publications: 0 publications found

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]

FGF8 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 6 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• hypogonadotropic hypogonadism

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000308881 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_033163.5 (FGF8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.5674 (below the threshold of 3.09). Trascript score misZ: 1.0113 (below the threshold of 3.09). GenCC associations: The gene is linked to holoprosencephaly, hypogonadotropic hypogonadism 6 with or without anosmia, congenital heart disease, hypogonadotropic hypogonadism, Kallmann syndrome.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033163.5. 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
	FGF8	NM_033163.5	MANE Select	c.469_471delGTCinsTTT	p.Val157Phe	missense	N/A	NP_149353.1	P55075-4
	FGF8	NM_033164.4		c.436_438delGTCinsTTT	p.Val146Phe	missense	N/A	NP_149354.1	P55075-1
	FGF8	NM_006119.6		c.382_384delGTCinsTTT	p.Val128Phe	missense	N/A	NP_006110.1	P55075-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF8	ENST00000320185.7	TSL:1 MANE Select	c.469_471delGTCinsTTT	p.Val157Phe	missense	N/A	ENSP00000321797.2	P55075-4
	FGF8	ENST00000344255.8	TSL:1	c.436_438delGTCinsTTT	p.Val146Phe	missense	N/A	ENSP00000340039.3	P55075-1
	FGF8	ENST00000347978.2	TSL:1	c.382_384delGTCinsTTT	p.Val128Phe	missense	N/A	ENSP00000321945.2	P55075-3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-103530350;