10-101770141-TAAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr10-101770141-TAAAAA-T
• rs11322844
• NM_033163.5:c.*183_*187delTTTTT

Variant summary

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

The NM_033163.5(FGF8):​c.*183_*187delTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 392,864 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: FGF8 NM_033163.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• 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
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5	c.*183_*187delTTTTT		3_prime_UTR_variant	Exon 6 of 6	ENST00000320185.7	NP_149353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7	c.*183_*187delTTTTT		3_prime_UTR_variant	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 4 AN: 120778 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000176 AC: 48 AN: 272086 Hom.: 0 AF XY: 0.000143 AC XY: 20 AN XY: 139712

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7498

American (AMR) AF: 0.000307 AC: 3 AN: 9776

Ashkenazi Jewish (ASJ) AF: 0.000110 AC: 1 AN: 9072

East Asian (EAS) AF: 0.000185 AC: 4 AN: 21652

South Asian (SAS) AF: 0.000198 AC: 3 AN: 15122

European-Finnish (FIN) AF: 0.000152 AC: 3 AN: 19694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1246

European-Non Finnish (NFE) AF: 0.000169 AC: 29 AN: 171388

Other (OTH) AF: 0.000301 AC: 5 AN: 16638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000331 AC: 4 AN: 120778 Hom.: 0 Cov.: 0 AF XY: 0.0000350 AC XY: 2 AN XY: 57200

African (AFR) AF: 0.0000633 AC: 2 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 12090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3022

East Asian (EAS) AF: 0.00 AC: 0 AN: 4236

South Asian (SAS) AF: 0.00 AC: 0 AN: 3748

European-Finnish (FIN) AF: 0.000209 AC: 1 AN: 4796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.0000171 AC: 1 AN: 58596

Other (OTH) AF: 0.00 AC: 0 AN: 1654

Alfa AF: 0.00 Hom.: 142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

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

Other links and lift over

dbSNP: rs11322844; hg19: chr10-103529898;