NM_033163.5:c.661G>A

Variant names:

• chr10-101770403-C-T
• rs1370886145
• NM_033163.5:c.661G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_033163.5(FGF8):​c.661G>A​(p.Glu221Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FGF8 NM_033163.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• 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: 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.

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.661G>A	p.Glu221Lys	missense	Exon 6 of 6	NP_149353.1	P55075-4
	FGF8	NM_033164.4		c.628G>A	p.Glu210Lys	missense	Exon 6 of 6	NP_149354.1	P55075-1
	FGF8	NM_006119.6		c.574G>A	p.Glu192Lys	missense	Exon 5 of 5	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.661G>A	p.Glu221Lys	missense	Exon 6 of 6	ENSP00000321797.2	P55075-4
	FGF8	ENST00000344255.8	TSL:1	c.628G>A	p.Glu210Lys	missense	Exon 6 of 6	ENSP00000340039.3	P55075-1
	FGF8	ENST00000347978.2	TSL:1	c.574G>A	p.Glu192Lys	missense	Exon 5 of 5	ENSP00000321945.2	P55075-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 232444 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454480 Hom.: 0 Cov.: 32 AF XY: 0.00000553 AC XY: 4 AN XY: 722972

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 43114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109182

Other (OTH) AF: 0.00 AC: 0 AN: 60072

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.028	D
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.38		Gain of methylation at E210 (P = 0.0013)
MVP		0.69
MPC		1.1
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.24
gMVP		0.40
Mutation Taster		=65/35	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: rs1370886145; hg19: chr10-103530160;