10-101770141-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

• chr10-101770141-TAAA-T
• rs11322844
• NM_033163.5:c.*185_*187delTTT

Variant summary

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

The NM_033163.5(FGF8):​c.*185_*187delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 388,074 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 0.000083 (0 hom., cov: 0)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: FGF8 NM_033163.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• 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.*185_*187delTTT		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.*185_*187delTTT		3_prime_UTR_variant	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes AF: 0.0000828 AC: 10 AN: 120776 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000827

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000834

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000683

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0206 AC: 5501 AN: 267316 Hom.: 0 AF XY: 0.0215 AC XY: 2950 AN XY: 137214

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

African (AFR) AF: 0.0122 AC: 90 AN: 7378

American (AMR) AF: 0.0283 AC: 271 AN: 9576

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 170 AN: 8880

East Asian (EAS) AF: 0.0162 AC: 344 AN: 21220

South Asian (SAS) AF: 0.0358 AC: 534 AN: 14902

European-Finnish (FIN) AF: 0.0228 AC: 440 AN: 19336

Middle Eastern (MID) AF: 0.0196 AC: 24 AN: 1224

European-Non Finnish (NFE) AF: 0.0195 AC: 3289 AN: 168422

Other (OTH) AF: 0.0207 AC: 339 AN: 16378

⚠️ 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: 0.0000828 AC: 10 AN: 120758 Hom.: 0 Cov.: 0 AF XY: 0.0000699 AC XY: 4 AN XY: 57200

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

African (AFR) AF: 0.0000316 AC: 1 AN: 31612

American (AMR) AF: 0.0000827 AC: 1 AN: 12094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3020

East Asian (EAS) AF: 0.00 AC: 0 AN: 4218

South Asian (SAS) AF: 0.00 AC: 0 AN: 3714

European-Finnish (FIN) AF: 0.000834 AC: 4 AN: 4798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0000683 AC: 4 AN: 58596

Other (OTH) AF: 0.00 AC: 0 AN: 1660

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000623984), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

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;