rs762175290

Positions:

• chr10-101775182-T-TCCCTGCCCAGCGCAGGGC

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_033163.5(FGF8):​c.103_104insGCCCTGCGCTGGGCAGGG​(p.Gly29_Arg34dup) variant causes a 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. 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 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 545463.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 259 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF8	NM_033163.5	c.103_104insGCCCTGCGCTGGGCAGGG	p.Gly29_Arg34dup	inframe_insertion	3/6	ENST00000320185.7	NP_149353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7	c.103_104insGCCCTGCGCTGGGCAGGG	p.Gly29_Arg34dup	inframe_insertion	3/6	1	NM_033163.5	ENSP00000321797	A2

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

GnomAD3 exomes AF: 0.00132 AC: 196 AN: 148156 Hom.: 1 AF XY: 0.00143 AC XY: 114 AN XY: 79872

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 SAS 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

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000671

Gnomad4 NFE exome AF: 0.00344

Gnomad4 OTH exome AF: 0.00138

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

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00174 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2023	In-frame insertion of 6 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 25131394, 26857713) -

Holoprosencephaly sequence Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Muenke lab, National Institutes of Health

Apr 20, 2018

While absent from public databases, this may be due to technical issues. At least 3 un-related probands (and one transmitting healthy parent) are positive for this missense change. Experimentally normal with ACMG criteria: BS3;PM2. No predictions for indel effects are given. -

FGF8-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypogonadotropic hypogonadism 6 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

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: rs762175290; hg19: chr10-103534939;