10-101775182-TCCCTGCCCAGCGCAGGGC-TCCCTGCCCAGCGCAGGGCCCCTGCCCAGCGCAGGGC

Variant names:

• chr10-101775182-T-TCCCTGCCCAGCGCAGGGC
• rs762175290
• NM_033163.5:c.86_103dupGCCCTGCGCTGGGCAGGG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_033163.5(FGF8):​c.86_103dupGCCCTGCGCTGGGCAGGG​(p.Gly29_Arg34dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,548,090 control chromosomes in the GnomAD database, including 13 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: FGF8 NM_033163.5 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.37
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_033163.5.
• BP6: Variant 10-101775182-T-TCCCTGCCCAGCGCAGGGC is Benign according to our data. Variant chr10-101775182-T-TCCCTGCCCAGCGCAGGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 545463.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0017 (259/152254) while in subpopulation NFE AF = 0.00338 (230/68000). AF 95% confidence interval is 0.00302. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD gene

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.86_103dupGCCCTGCGCTGGGCAGGG	p.Gly29_Arg34dup	conservative_inframe_insertion	Exon 3 of 6	NP_149353.1	P55075-4
	FGF8	NM_033164.4		c.86_103dupGCCCTGCGCTGGGCAGGG	p.Gly29_Arg34dup	conservative_inframe_insertion	Exon 3 of 6	NP_149354.1	P55075-1
	FGF8	NM_006119.6		c.70-288_70-271dupGCCCTGCGCTGGGCAGGG		intron	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.86_103dupGCCCTGCGCTGGGCAGGG	p.Gly29_Arg34dup	conservative_inframe_insertion	Exon 3 of 6	ENSP00000321797.2	P55075-4
	FGF8	ENST00000344255.8	TSL:1	c.86_103dupGCCCTGCGCTGGGCAGGG	p.Gly29_Arg34dup	conservative_inframe_insertion	Exon 3 of 6	ENSP00000340039.3	P55075-1
	FGF8	ENST00000347978.2	TSL:1	c.70-288_70-271dupGCCCTGCGCTGGGCAGGG		intron	N/A	ENSP00000321945.2	P55075-3

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00132 AC: 196 AN: 148156 AF XY: 0.00143

Gnomad AFR exome AF: 0.000575

Gnomad AMR exome AF: 0.0000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000527

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.000946

GnomAD4 exome AF: 0.00275 AC: 3845 AN: 1395836 Hom.: 13 Cov.: 32 AF XY: 0.00272 AC XY: 1870 AN XY: 688444

African (AFR) AF: 0.000539 AC: 17 AN: 31540

American (AMR) AF: 0.0000840 AC: 3 AN: 35726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79154

European-Finnish (FIN) AF: 0.000671 AC: 32 AN: 47674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4166

European-Non Finnish (NFE) AF: 0.00344 AC: 3713 AN: 1078860

Other (OTH) AF: 0.00138 AC: 80 AN: 57808

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152254 Hom.: 0 Cov.: 31 AF XY: 0.00145 AC XY: 108 AN XY: 74454

African (AFR) AF: 0.000385 AC: 16 AN: 41558

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00174 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	FGF8-related disorder (1)
-	1	-	Holoprosencephaly sequence (1)
-	-	1	Hypogonadotropic hypogonadism 6 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=75/25	polymorphism

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

dbSNP: rs762175290; hg19: chr10-103534939;