NM_033163.5:c.118T>C

Variant names:

• chr10-101775168-A-G
• rs137852661
• NM_033163.5:c.118T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_033163.5(FGF8):​c.118T>C​(p.Phe40Leu) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGF8 NM_033163.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.287
• Publications: 4 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
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 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 hypogonadotropic hypogonadism, holoprosencephaly, hypogonadotropic hypogonadism 6 with or without anosmia, Kallmann syndrome.
• PP5: Variant 10-101775168-A-G is Pathogenic according to our data. Variant chr10-101775168-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9123.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.336237). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF8	NM_033163.5	MANE Select	c.118T>C	p.Phe40Leu	missense	Exon 3 of 6	NP_149353.1
	FGF8	NM_033164.4		c.118T>C	p.Phe40Leu	missense	Exon 3 of 6	NP_149354.1
	FGF8	NM_006119.6		c.70-256T>C		intron	N/A	NP_006110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF8	ENST00000320185.7	TSL:1 MANE Select	c.118T>C	p.Phe40Leu	missense	Exon 3 of 6	ENSP00000321797.2
	FGF8	ENST00000344255.8	TSL:1	c.118T>C	p.Phe40Leu	missense	Exon 3 of 6	ENSP00000340039.3
	FGF8	ENST00000347978.2	TSL:1	c.70-256T>C		intron	N/A	ENSP00000321945.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypogonadotropic hypogonadism 6 with or without anosmia Pathogenic:1

Aug 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.29
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.46
Sift	Benign	0.84	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.33		Gain of helix (P = 0.0696)
MVP		0.96
MPC		0.96
ClinPred		0.042	T
GERP RS		-4.0
Varity_R		0.038
gMVP		0.53
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs137852661; hg19: chr10-103534925;